Composition and method for treatment of symptoms associated with various skin conditions

ABSTRACT

Compositions containing imidazole-based compounds, and optionally, colloidal oatmeal, for the treatment, prevention, and management of symptoms, conditions, diseases, and disorders of the skin. Also, methods for the treatment, prevention, and management of symptoms, conditions, diseases, and disorders of the skin using compositions containing imidazole-based compounds, and optionally, colloidal oatmeal.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application, claiming benefit 35 U.S.C.§ 120 of U.S. application Ser. No. 14/230,494, filed Mar. 31, 2014,which claims the benefit under 35 U.S.C. §§ 120 and 365(c) of PCTInternational Application No. PCT/US2012/057431, filed Sep. 27, 2012,and claiming benefit under 35 U.S.C. § 119(e) of U.S. ProvisionalApplication No. 61/540,953, filed Sep. 29, 2011. The disclosures of U.S.application Ser. No. 14/230,494, PCT International Application No.PCT/US2012/057431, and U.S. Provisional Application No. 61/540,953 areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to compositions containing imidazole-basedcompounds, and optionally, colloidal oatmeal, and to methods of theiruse for the treatment, prevention, and management of symptoms,conditions, diseases, and disorders of the skin.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a method of treating, managing,or preventing a dermatological or skin condition, which comprisestopically administering to a subject in need thereof a therapeuticallyor prophylactically effective composition comprising an imidazolecompound of the formula:

wherein:

-   -   R₁ is hydrogen, alkyl or aryl;    -   R₆ is OR₁₀ or OC(O)R₁₀;    -   R₇ is OR₁₁ or OC(O)R₁₁;    -   R₈ is OR₁₂ or OC(O)R₁₂; and    -   R₉ is hydrogen, CH₂OR₁₃ or CH₂OC(O)R₁₃; and each of R₁₀, R₁₁,        R₁₂ and R₁₃ is independently hydrogen or lower alkyl,        and pharmaceutically, dermatologically, or cosmetically        acceptable salts thereof.

Another aspect of the invention relates to a method of caring for skin,which comprises topically administering to the skin of a subject in needthereof a composition comprising the imidazole compound in an amount andfor a time sufficient to effect a change in the skin.

Another aspect of the invention relates to a method of delivering ordepositing a benefit agent onto skin, which comprises topicallyadministering to the skin of a subject a composition comprising theimidazole compound contained in a dermatologically acceptable carrier.

Another aspect of the invention relates to a method of suppressing adermatologic immune response in a patient in need thereof, comprisingtopically administering an effective composition comprising theimidazole compound contained in a dermatologically acceptable carrier.Another aspect of the invention relates to a composition comprising animidazole

compound of the formula:

wherein:

-   -   R₁ is hydrogen, alkyl or aryl;    -   R₆ is OR₁₀ or OC(O)R₁₀;    -   R₇ is OR₁₁ or OC(O)R₁₁;    -   R₈ is OR₁₂ or OC(O)R₁₂; and    -   R₉ is hydrogen, CH₂OR₁₃ or CH₂OC(O)R₁₃; and each of R₁₀, R₁₁,        R₁₂ and R₁₃ is independently hydrogen or lower alkyl,        and pharmaceutically, dermatologically, or cosmetically        acceptable salts thereof.

Another aspect of the invention relates to compositions containingcombinations of imidazole-based compounds and, optionally, colloidaloatmeal, and to methods of their use for the treatment, prevention, andmanagement of inflammatory or immune-mediated symptoms, conditions,diseases, and disorders of the skin.

Another aspect of the invention relates to combinations ofimidazole-based compounds and, optionally, colloidal oatmeal, and tomethods of their use for the treatment, prevention, and management ofvarious skin symptoms, conditions, diseases, and disorders.

Another aspect of the invention relates to combinations ofimidazole-based compounds and colloidal oatmeal and to methods of theiruse for the treatment, prevention, and management of atopic dermatitis,seborrheic dermatitis, contact dermatitis, cutaneous sarcoidosis, druginduced photosensitivity, fixed drug eruptions, id reactions, bullousskin diseases, discoid lupus erythematosus, subacute cutaneous lupus,alopecia areata, sea bathers eruptions, psoriasis, dyshidrotic eczema,and pompholyx.

Another aspect of the invention relates to compositions and methods fortreating inflammatory and/or immune-mediated dermatoses withimidazole-based compounds and combinations of imidazole-based compoundsand colloidal oatmeal.

Another aspect of the invention relates to care, supplement, andpharmaceutical compositions containing imidazole-based compounds,colloidal oatmeal, and other ingredients used to treat disorders of theskin, as well as to compositions suitable for use in personal careapplications, and in particular skin care compositions, whicheffectively deliver and/or deposit various benefit agents into and ontothe skin.

Another aspect of the invention relates to compositions and methods fortreating contact dermatitis.

These and further aspects of the claimed invention will now be explainedin more detail.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise indicated, the term “alkyl” means a straight chain,branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20(e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to4 carbons are referred to as “lower alkyl.” Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyland dodecyl. Cycloalkyl moieties may be monocyclic or multicyclic, andexamples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andadamantyl. Additional examples of alkyl moieties have linear, branchedand/or cyclic portions (e.g., 1-ethyl-4-methyl-cyclohexyl). The term“alkyl” includes saturated hydrocarbons as well as alkenyl and alkynylmoieties.

Unless otherwise indicated, the terms “manage,” “managing” and“management” encompass preventing the recurrence of the specifieddisease or disorder in a patient who has already suffered from thedisease or disorder, and/or lengthening the time that a patient who hassuffered from the disease or disorder remains in remission. The termsencompass modulating the threshold, development and/or duration of thedisease or disorder, or changing the way that a patient responds to thedisease or disorder.

Unless otherwise indicated, the terms “prevent,” “preventing” and“prevention” contemplate an action that occurs before a patient beginsto suffer from the specified disease or disorder, which inhibits orreduces the severity of the disease or disorder. In other words, theterms encompass prophylaxis.

Unless otherwise indicated, a “prophylactically effective” meanssufficient to prevent a disease or condition, or one or more symptomsassociated with the disease or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease. Theterm “prophylactically effective” can encompass a composition thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

Unless otherwise indicated, a “therapeutically effective” meanssufficient to provide a therapeutic benefit in the treatment ormanagement of a disease or condition, or to delay or minimize one ormore symptoms associated with the disease or condition. Atherapeutically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other therapies, whichprovides a therapeutic benefit in the treatment or management of thedisease or condition. The term “therapeutically effective” can encompassa composition that improves overall therapy, reduces or avoids symptomsor causes of a disease or condition, or enhances the therapeuticefficacy of another therapeutic agent.

Unless otherwise indicated, the terms “treat,” “treating” and“treatment” contemplate an action that occurs while a patient issuffering from the specified disease or disorder, which reduces theseverity of the disease or disorder, or retards or slows the progressionof the disease or disorder.

Unless otherwise indicated, the term “include” has the same meaning as“include, but are not limited to,” and the term “includes” has the samemeaning as “includes, but is not limited to.” Similarly, the term “suchas” has the same meaning as the term “such as, but not limited to.”

Unless otherwise indicated, one or more adjectives immediately precedinga series of nouns is to be construed as applying to each of the nouns.For example, the phrase “optionally substituted A, B, or C” has the samemeaning as “optionally substituted A, optionally substituted B, oroptionally substituted C.”

It should be noted that a chemical moiety that forms part of a largercompound may be described herein using a name commonly accorded it whenit exists as a single molecule or a name commonly accorded its radical.

It should also be noted that if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or the portion of the structure is to beinterpreted as encompassing all stereoisomers of it. Moreover, any atomshown in a drawing with unsatisfied valences is assumed to be attachedto enough hydrogen atoms to satisfy the valences.

As used herein, the term “benefit agent” includes any active ingredientthat is to be delivered into and/or onto the skin at a desired location,such as a cosmetic, care or pharmaceutical agent, and that is capable ofproviding a cosmetic, care, or therapeutic effect.

By “cosmetic agent,” it is meant any ingredient that is appropriate forcosmetically treating, providing nutrients to, and/or conditioning thehair, nail, and/or skin via topical application.

By “pharmaceutical agent,” it is mean any drug that is eitherhydrophobic or hydrophilic in nature and appropriate for topical use.

As used herein “medicament agents” include those agents capable ofpromoting recovery from injury and illness.

As used herein “pharmaceutically, dermatologically, or cosmeticallyacceptable” means that the ingredients which the term describes aresuitable for use in contact with the skin without undue toxicity,incompatibility, instability, irritation, allergic response, and thelike.

Other than where otherwise indicated, or where required to distinguishover the prior art, all numbers expressing quantities of ingredientsherein are to be understood as modified in all instances by the term“about”. As used herein, the words “may” and “may be” are to beinterpreted in an open-ended, non-restrictive manner. At minimum, “may”and “may be” are to be interpreted as definitively including, but notlimited to, the composition, structure, or act recited.

As used herein, and in particular as used herein to define the elementsof the claims that follow, the articles “a” and “an” are synonymous andused interchangeably with “at least one” or “one or more,” disclosing orencompassing both the singular and the plural, unless specificallydefined herein otherwise. The conjunction “or” is used herein in both inthe conjunctive and disjunctive sense, such that phrases or termsconjoined by “or” disclose or encompass each phrase or term alone aswell as any combination so conjoined, unless specifically defined hereinotherwise.

The description of a group or class of materials as suitable orpreferred for a given purpose in connection with the invention impliesthat mixtures of any two or more of the members of the group or classare equally suitable or preferred. Description of constituents inchemical terms refers unless otherwise indicated, to the constituents atthe time of addition to any combination specified in the description,and does not necessarily preclude chemical interactions among theconstituents of a mixture once mixed. Steps in any method disclosed orclaimed need not be performed in the order recited, except as otherwisespecifically disclosed or claimed.

Changes in form and substitution of equivalents are contemplated ascircumstances may suggest or render expedient. Although specific termshave been employed herein, such terms are intended in a descriptivesense and not for purposes of limitation.

Methods of Treatment

The general form of treatment for dermatoses according to the inventionis chemical therapy by topical administration of the benefit agent oragents. Topical medications may be delivered to the affected site bymeans including but not limited to baths, soaps, shampoos, wet dressingsor soaks, powders, pastes, tinctures, shake lotions, aerosols, foams,medicated tape, transdermal devices, creams, ointments, oils, andemulsions.

Generally, the composition is topically applied to the affected skinareas in a predetermined or as-needed regimen to bring aboutimprovement, it generally being the case that gradual improvement isnoted with each successive application. Insofar as has been determinedbased upon studies to date, no adverse side effects are encountered.

In treating atopic dermatitis, psoriasis, eczema, or any of theconditions or indications disclosed herein, an ointment or lotionaccording to aspects of the invention containing 0.01% to 10% by weightof the imidazole compound and, optionally, 0.01% to 25% of colloidaloatmeal is applied to the affected area of the skin. The upper limit ofthe imidazole compound may preferably be 9%, 8%, 7%, 6%, 5%, 4%, 3%,2.5%, 2%, or even 1.5% by weight of the ointment or lotion, and thelower limit of the imidazole compound may preferably be 0.01%, 0.05%,0.1%, 0.2%, 0.3%, 0.4%, or even 0.5% by weight of the ointment orlotion. Preferably the ointment or lotion comprises 1.0% by weight ofthe imidazole compound. The upper limit of the colloidal oatmeal maypreferably be 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2.5%, 2%,or even 1.5% by weight of the ointment or lotion, and the lower limit ofthe colloidal oatmeal may preferably be 0.01%, 0.05%, 0.1%, 0.2%, 0.3%,0.4%, or even 0.5% by weight of the ointment or lotion. Preferably theointment or lotion comprises 1.0% by weight of the colloidal oatmeal.The patient may be treated, for example, daily for two to four weekswith a dosage amount of 5 mg to 10 mg of imidazole compound and 5 mg to10 mg of colloidal oatmeal a day. The topically effective amounts ofimidazole compound are typically 0.5% to 2% by weight and of thecolloidal oatmeal 0.5%% to 2% by weight in an ointment or lotion and areapplied one to three times a day for a period of time, typically weeks,to effectively treat the dermatoses.

Under certain circumstances, it is desirable to administer the imidazolecompound and colloidal oatmeal simultaneously with otherdermatologically active agents. The precise amount of imidazole compoundand colloidal oatmeal used alone or with other dermatologic agentsvaries depending, for example, on the condition for which thecomposition is administered. The amount, route of administration anddosing schedule will depend upon factors such as the specific indicationto be treated, prevented, or managed, and the age, sex and condition ofthe patient. The roles played by such factors are well known in the art,and may be accommodated by routine experimentation. One skilled in theart can adjust the dosage forms to achieve the desired therapeuticlevels.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers may be used to assist in delivering active ingredients to thetissue.

Another embodiment of the present invention is directed to a method fordepositing a benefit agent onto the skin to a desired location on ahuman or animal. While the frequency and amount of the benefitagent-containing composition to be applied will depend upon, forexample, the type and amount of benefit agent available, the intendedusage of the final composition, i.e. therapeutic versus maintenanceregimen, and the sensitivity of the individual user to the composition,typically the benefit agent-containing composition of the presentinvention should be topically applied to affected body parts at regularintervals, and preferably twice daily, in the morning and evening. Thecomposition may be applied more frequently during the initial stages oftreatment, until the desired effect is achieved, then less frequentlywhen maintenance is desired.

Conditions Treated

The methods according to the invention can be used to treat a variety ofskin conditions, which result in inflammation or erythema. For example,inflammation or erythema can result from external causes such as sun orwind burn or irritating soaps or cleansers. It is also known thatinflammation and erythema can be caused from inherent conditions such asrosacea, atopic dermatitis, or allergic skin reactions. The methodaccording to the invention can be used to treat inflammation and/orerythema caused by both external and inherent conditions.

Another aspect of the invention relates to combinations ofimidazole-based compounds and colloidal oatmeal and to methods of theiruse for the treatment, prevention, and management of atopic dermatitis,seborrheic dermatitis, contact dermatitis, cutaneous sarcoidosis, druginduced photosensitivity, fixed drug eruptions, id reactions, bullousskin diseases, discoid lupus erythematosus, subacute cutaneous lupus,alopecia areata, sea bathers eruptions, psoriasis, dyshidrotic eczema,and Pompholyx. This list of examples of dermatological conditions, forwhich the therapy as proposed in this application is useful, does notlimit the present invention to these indications, since there may beother dermatological conditions not mentioned here where combinations ofimidazole-based compounds and colloidal oatmeal may also be effective.Thus, further non-limiting examples of conditions to which the presentinvention may be applied include:

-   -   (a) dermatologic allergies, such as contact dermatitis,        photoallergic dermatitis; industrial dermatoses caused by        exposure to a variety of compounds used by industry that are        contact irritants; atopic eczema (infantile and adult),        dermatoses caused by drugs and nummular eczema;    -   (b) immune-mediated skin diseases, suchbullous pemphigoid,        pemphigus vulgaris, necrotizing vasculitis, lupus erythematosus        (discoid and systemic), dermatitis herpetiformis;    -   (B2) immune, non-immune, or autoimmune urticarias such as        allergic urticaria, chronic idiopathic urticaria, solar        urticaria, cholinergic urticaria, pressure urticaria, cold        urticaria, dermatographia, and pruritic urticarial papules and        plaques of pregnancy (PUPPP);    -   (B3) mastocytosis;    -   (c) pruritic dermatoses, such as winter, senile, and essential        pruritus, pruritus ani, external otitis, and genital pruritus;    -   (d) vascular dermatoses, such as erythema multiforme, erythema        nodosum, stasis dermatitis, purpuric dermatoses such as        thrombocytopenic purpura and Henoch-Schonlein purpura,        ecchymoses, stasis purpura, primary and secondary        telangiectases;    -   (e) seborrheic dermatitis, acne, and rosacea;    -   (f) papulosquamous dermatoses: such as psoriasis, pityriasis        rosea, lichen planus;    -   (g) bacterial dermatoses, such as pyoderma, impetigo, ecthyma,        folliculitis, furuncles styes, carbuncles, sweat gland        infections, erysipelas, erythrasma, infected ulcers, and        infected eczematoid dermatitis;    -   (h) systemic bacterial infections with skin manifestations, such        as scarlet fever, granuloma inguinale, chancroid, tuberculosis,        leprosy, gonorrhea, rickettsial diseases, actinomycosis,        syphilis;    -   (i) viral skin infection, such as those caused by herpes simplex        virus, Kaposi's varicelliform eruption, zoster, chickenpox,        smallpox, vaccinia, cowpox, warts, molluscum contagiosum,        lymphogranuloma venereum, exanthematous diseases such as German        measles, roseola and erythema infectiosum;    -   (j) mycolic skin infections, such as tinea (superficial fungal        infections of the skin in various body sites), sporotrichosis,        North American blastomycosis;    -   (k) granulomatous dermatoses, such as sarcoidosis, granuloma        annulare, silica induced granulomas;    -   (l) parasitic skin infections, such as scabies, pediculosis;    -   (m) bullous dermatoses;    -   (n) exfoliative dermatitis, primary and secondary;    -   (o) pigmented dermatoses, such as chloasma (melasma) and        vitiligo;    -   (p) collagen diseases, such as lupus erythematosus, scleroderma,        dermatomyositis;    -   (q) dermatoses due to internal diseases, such as Kaposi's        sarcoma, pyoderma gangrenosum associated with ulcerative        colitis, ulcers due to diabetes, xanthomas;    -   (r) diseases of mucous membranes, such as aphthous ulcers;    -   (s) dermatoses due to physical agents, such as sunburns and        radiation; and    -   (t) photosensitive dermatoses of the exogenous-type, such as        drug-induced photodermatitis, contact dermatitis with        photoallergic components, and of the endogenous-type, such as        porphyrias, collagen vascular disorders such as lupus        erythematosus, dermatomyositis, and polymorphous light        eruptions.

Contact dermatitis is a steroid responsive condition and is caused byplant saps (poison ivy, etc) and chemicals. About 80% are irritant typewhile 20% are allergic. There are over 85,000 chemicals estimated toexist in the modern environment. Any might cause contact dermatitis. Themost common allergic sensitizers are nickel sulfate, fragrances,thimerosal, quartemium-15, neomycin sulfate, formaldehyde, bacitracin,thiuram mix, balsam of Peru, cobalt chloride, p-phenylenediamine, andcarba mix. Other steroid responsive dematoses might include seborrheicdermatitis, diaper rash, and bullous skin diseases such as bullouspemphigoid.

Further examples of diseases and disorders include ankylosingspondylitis, asthma (e.g., bronchial asthma), atopic dermatitis,Behcet's disease, graft-vs-host disease, Kawasaki syndrome, lupuserythematosus, multiple sclerosis, myasthenia gravis, pollinosis,psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma,transplant rejection (e.g., of organ, cell or bone marrow), type 1diabetes, and uveitis. Additional diseases and disorders includeAddison's Disease, anti-phospholipid syndrome, autoimmune atrophicgastritis, achlorhydra autoimmune, Celiac Disease, Crohn's Disease,Cushing's Syndrome, dermatomyositis, Goodpasture's Syndrome, Grave'sDisease, Hashimoto's thyroiditis, idiopathic adrenal atrophy, idiopathicthrombocytopenia, Lambert-Eaton Syndrome, pemphigoid, pemphigusvulgaris, pernicious anemia, polyarteritis nodosa, primary biliarycirrhosis, primary sclerosing cholangitis, Raynauds, Reiter's Syndrome,relapsing polychondritis, Schmidt's Syndrome, Sjogren's Syndrome,sympathetic ophthalmia, Takayasu's Arteritis, temporal arteritis,thyrotoxicosis, ulcerative colitis, and Wegener's granulomatosis.

Further indications addressed by the compositions and methods of theinvention include, for example, immunosuppression (e.g., employing oneor more agents such as cyclosporin A, QKT3, FK506, mycophenolate mofetil(MMF), azathioprine, corticosteroids (such as prednisone),antilymphocyte globulin, antithymocyte globulin, and the like),

inflammatory disease therapy (e.g., employing disease-modifying agents(such as antimalarials, methotrexate, sulfasalazine, mesalamine,azathioprine, 6-mercaptopurine, metronidazole, injectable and oral gold,D-penicillamine, and the like), corticosteroids, non-steroidalantiinflammatory drugs (such as aspirin, sodium salicylate, magnesiumsalicylate, choline magnesium salicylate, salicylsalicylic acid,ibuprofen, naproxen, diclofenac, diflunisal, etodolac, fenoprofencalcium, fluriprofen, piroxicam, indomethacin, ketoprofen, ketorolactromethamine, meclofenamate, meclofenamate sodium, mefenamic acid,nabumetone, oxaprozin, phenyl butyl nitrone (PBN), sulindac, tolmetin,and the like), and the like),anti-cancer therapy (e.g., employing one or more agents such asalkylating agents (such as mechlorethamine, chlorambuccil, ifosfamide,melphalan, busulfan, carmustine, lomustine, procarbazine, dacarbazine,cisplatin, carboplatin, and the like), antimetabolites (such asmethotrexate, mercaptopurine, thioguanine fluorouracil, cytarabine, andthe like), hormonal agents (such as testosterone propionate,fluoxymesterone, flutamide, diethylstilbestrol, ethinyl estradiol,tamoxifen, hydroxyprogesterone caproate, medroxyprogesterone, megestrolacetate, and the like), adrenocorticosteroids (such as prednisone),aromatase inhibitors (such as amino glutethimide), leuprolide, goserelinacetate, biological response modifiers (such as interferon-.alpha.2a,interferon-.alpha.2b, interleukin-2, and the like), peptide hormoneinhibitors (such as octreotide acetate), natural products (such asvinblastine, vincristine, vinorelbine, paclitaxel, dactinomycin,daunorubicin, idarubicin, doxorubicin, etoposide, plicamycin, mitomycin,mitoxantrone, bleomycin, hydroxyurea, mitotane, fludarabine, cladribine,and the like), supportive agents (such as allopurinol, mesna,leucovorin, erythropoietin, filgrastim, sargramostim, and the like), andthe like, anti-microbial therapy (e.g., employing one or more agentssuch as celftriaxone, TMP-SMZ, penicillin, aminoglycosides, vancomycin,gentamicin, rifampin, imipenem, clindamycin, metronidazole,tetracycline, erythromycin, sulfonamide, streptomycin, ampicillin,isoniazid, pyrazinamide, ethambutol, and the like), anti-fungal therapy(e.g., employing agents such as amphotericin B, griseofulvin, myastatin,flucytosine, natamycin, antifungal imidazoles (e.g., clotrimazole,miconazole, ketoconazole, fluconazole, itraconazole, and the like), andthe like, anti-retroviral therapy (e.g., employing agents such asprotease inhibitors (such as Invirase, Ritonavir, Crixivan, and thelike), zidovudine, didanosine, zalcitabine, stavudine, viramune, and thelike), and treatment of cellular proliferative diseases (e.g., oncolyticviral therapy employing naturally occurring and/or modified oncolyticviruses such as reovirus, adenovirus, seneca valley virus, vesicularstomatitis virus, poliovirus, vacina virus, herpes virus and the like),and treatment of opportunistic infections and malignancies (e.g.,anti-AIDS treatment, employing agents such as pentamidine,trimethoprim/sulfamethoxazole, primaquine, atovaquope, clarithromycin,clofazimine, ethambutol, rifampin, amikacin, ciprofloxacin,pyrimethamine, amphotericin B, ganciclovir, foscarnet, fluconazole,ketoconazole, acyclovir, and the like).Benefit Agents

A first element of the compositions and methods according to aspects ofthe invention is an imidazole compound of the formula:

wherein:

-   -   R₁ is hydrogen, alkyl or aryl;    -   R₆ is OR₁₀ or OC(O)R₁₁;    -   R₇ is OR_(H) or OC(O)R₁₁;    -   R₈ is OR₁₂ or OC(O)R₁₂; and    -   R₉ is hydrogen, CH₂OR₁₃ or CH₂OC(O)R₁₃; and each of R₁₀, R₁₁,        R₁₂ and R₁₃ is independently hydrogen or lower alkyl.

The compounds of the preceding formula of the present invention may alsobe present in the form of pharmaceutically, dermatologically, orcosmetically acceptable salts thereof that can be made by conventionaltechniques.

Pharmaceutically, dermatologically, or cosmetically acceptableacidic/anionic salts include, and are not limited to acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphospate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate and triethiodide.

Pharmaceutically, dermatologically, or cosmetically acceptablebasic/cationic salts include, and are not limited to aluminum,benzathine, calcium, chloroprocaine, choline, diethanolamine,ethylenediamine, lithium, magnesium, meglumine, potassium, procaine,sodium and zinc. Other salts may, however, be useful in the preparationof compounds according to this invention or of their cosmeticallyacceptable salts. Organic or inorganic acids also include, and are notlimited to, hydriodic, perchloric, sulfuric, phosphoric, propionic,glycolic, methanesulfonic, hydroxyethanesulfonic, oxalic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,saccharinic or trifluoroacetic acid.

In particular embodiments, the imidazole compound is2-acetyl-4-tetrahydroxybutylimidazole (THI). THI is a component ofcaramel color III and has been identified as a sphingosine-1-phosphatelyase antagonist. Sphingosine-1-phosphate (SIP) is a bioactive moleculewith effects on multiple organ systems. Sphingosine-1-phosphate lyase isa vitamin B6-dependent enzyme localized in the membrane of theendoplasmic reticulum. Van Veldhoven and Mannaerts, J. Biol. Chem.266:12502-12507 (1991); Van Veldhoven and Mannaerts, Adv. Lipid. Res.26:69 (1993). The polynucleotide and amino acid sequences of human SP1lyase and its gene products are described in PCT Patent Application No.WO 99/16888.

THI inhibits S1P lyase activity when administered to mice. Schwab, S. etal., Science 309:1735-1739 (2005). Administration of the compound torats and mice induces lymphopenia and causes the accumulation of matureT cells in the thymus. See, e.g., Schwab, supra; Pyne, S. G., ACGC Chem.Res. Comm. 11:108-112 (2000); Gugasyan, R., et al., Immunology93(3):398-404 (1998); Halweg, K. M. and Büchi, G., J. Org. Chem.50:1134-1136 (1985); U.S. Pat. No. 4,567,194 to Kroeplien and Rosdorfer.Still, there are no known reports of THI having an immunological effectin animals other than mice and rats. Although U.S. Pat. No. 4,567,194alleges that THI and some related compounds may be useful asimmunosuppressive medicinal agents, studies of the compound in humanshave found no immunological effects. See Thuvander, A. and Oskarsson,A., Fd. Chem. Toxic. 32(1):7-13 (1994); Houben, G. F., et al., Fd. Chem.Toxic. 30(9):749-757 (1992).

Compounds of the invention may contain one or more stereocenters, andcan exist as racemic mixtures of enantiomers or mixtures ofdiastereomers. This invention encompasses stereomerically pure forms ofsuch compounds, as well as mixtures of those forms. Stereoisomers may beasymmetrically synthesized or resolved using standard techniques such aschiral columns or chiral resolving agents. See, e.g., Jacques, J., etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); andWilen, S. H., Tables of Resolving Agents and Optical Resolutions, p. 268(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).This invention further encompasses stereoisomeric mixtures of compoundsdisclosed herein. It also encompasses configurational isomers ofcompounds disclosed herein, either in admixture or in pure orsubstantially pure form.

Compounds of the invention can be prepared by methods known in the art(e.g., by varying and adding to the approaches described in Pyne, S. G.,ACGC Chem. Res. Comm. 11:108-112 (2000); Halweg, K. M. and Büchi, G., J.Org. Chem. 50:1134-1136 (1985)). Compounds can also be made by themethods disclosed below and variants thereof, which will be apparent tothose of ordinary skill in the art.

The compositions according to the invention preferably contain theimidazole-based compound in an amount of 0.001% to 10%, more preferably0.5% to 2%, and most preferably about 1% by weight of the composition.The imidazole-based compound may also preferably be included in anamount of 0.01% to 10%, 0.1% to 10%, 0.1% to 9%, 0.1% to 8%, 0.1% to 7%,0.1% to 6%, 0.1% to 5%, 0.2% to 5%, 0.3% to 5%, 0.4% to 5%, 0.5% to 5%,0.5% to 4%, and 0.5% to 3% by weight of the composition.

A further element of preferred compositions and methods according toaspects of the invention is colloidal oatmeal. Oatmeal has been used asa soothing agent to relieve itch and irritation associated with variousxerotic dermatoses. In 1945, a ready to use colloidal oatmeal, producedby finely grinding the oat and boiling it to extract the colloidalmaterial, became available. Today, colloidal oatmeal is available invarious dosage forms from powders for the bath to shampoos, shavinggels, and moisturizing creams. Currently, the use of colloidal oatmealas a skin protectant is regulated by the U.S. Food and DrugAdministration (FDA) according to the Over-The-Counter Final Monographfor Skin Protectant Drug Products issued in June 2003. Its preparationis also standardized by the United States Pharmacopeia.

The many clinical properties of colloidal oatmeal derive from itschemical polymorphism. The high concentration in starches andbeta-glucan is responsible for the protective and water-holdingfunctions of oat. The presence of different types of phenols confersantioxidant and anti-inflammatory activity. Some of the oat phenols arealso strong ultraviolet absorbers. The cleansing activity of oat ismostly due to saponins. Its many functional properties make colloidaloatmeal a cleanser, moisturizer, buffer, as well as a soothing andprotective anti-inflammatory agent. Colloidal oatmeal may act at thesite of application to control the osmotic pressure of water withrespect to the skin and permits adequate water to enter into the stratumcorneum. Oatmeal may leave an occlusive film on the skin that serves tohold in moisture, which protects the skin against irritation and acts asan antipruritic.

Colloidal oatmeal includes the powder resulting from the grinding andfurther processing of whole oat grain meeting United States Standardsfor Number 1 or Number 2 oats. A suitable colloidal oatmeal has aparticle size distribution as follows: not more than 3 percent of thetotal particles exceed 150 micrometers in size and not more than 20percent of the total particles exceed 75 micrometers in size. Examplesof suitable colloidal oatmeals include, but are not limited to, “Tech-O”colloidal oatmeals (e.g., Tech-O #11-065 colloidal oatmeal) availablefrom the Beacon Corporation and colloidal oatmeals available fromQuaker. A USP grade of colloidal oatmeal suitable for use in thisinvention may be obtained under the mark “Tech-O” from Beacon CMPCorporation, 611 Springfield Road, Kenilworth, N.J. 07033.

The compositions may further contain one or more benefit agents orpharmaceutically-acceptable salts thereof. The benefit agents usefulherein may be categorized by their therapeutic benefit or theirpostulated mode of action. However, it is to be understood that thebenefit agents useful herein may, in some circumstances, provide morethan one therapeutic benefit or operate via greater than one mode ofaction. Therefore, the particular classifications provided herein aremade for the sake of convenience and are not intended to limit thebenefit agents to the particular application(s) listed. In addition, thecompounds, which are identified below as being suitable for use asbenefit agents, may be used in an amount over and above the amount thatthey may be used for other purposes in the compositions of theinvention.

Further benefit agents useful in the methods and compositions of theinvention include antipruritics, emollients, antiseptics, antifungals,antiinflammatories, immunosuppressants, psoriasis agents, anti-canceragents, antibiotics, antiparasitics, antioxidants, antibacterials,antimicrobials, antiretrovirals, moisturizers, sunscreens, NSAIDs,hormones, steroids, analgesics, antihistamines, and antipyretics. Thefollowing chemotherapeutic agents used to treat dermatoses are notcomprehensive but rather consist of examples of commonly used groups ofdrugs.

The antihistamines added to the topical compositions are typically fromthe structural classes of ethylenediamines, aminoalkylethers, andalkylamines. Among the ethylenediamine group are such antihistamines asantazoline phosphate, clemizole hydrochloride, chlorcyclizinehydrochloride, chlorothen, methapheniline hydrochloride, dorastinehydrochloride, methdilazine hydrochloride, promethazine hydrochloride,pyrathiazine hydrochloride, pyrilamine maleate, quinetolate, thenaldine,thenyldiamine hydrochloride, thonzylamine hydrochloride, tripelennamine,and zolamine hydrochloride. Among the aminoalkylether group are suchantihistamines as chlorphenoxamine hydrochloride, carbinoxamine maleate,clemastine, diphenhydramine hydrochloride, diphenylpyralinehydrochloride, doxylamine succinate, and pyroxamine maleate. Among thealkamine group are such antihistamines as azatadine maleate,bromdiphenhydramine hydrochloride, cyproheptadine hydrochloride,dimethindene maleate, phenindamine tartrate, pheniramine maleate,brompheniramine maleate, dexbrompheniramine maleate, chlorpheniraminemaleate, dex-chlorpheniramine maleate, closiramine, cycliramine maleate,mianserin hydrochloride, pyrrobutamine phosphate, terfenadine, andtriprolidine hydrochloride. Besides the above, some compositions instructural groups, which groups are not primarily antihistamines such asphenothiazines, piperidines, and piperazines, have antihistaminiccharacteristics. These groups include promethazine, astemizole,fexofenadine, loratadine, desloratadine, terfenadine, cetirizine, andmeclizin, which are antihistaminic.

Another active ingredient used in the formulations hereof is theemployment of a topical anesthetic. While some of these topicalanesthetic compounds are structurally related to the antihistamines inthe preceding paragraph, the compounds take on a disinct role inpreparations described. The first group are esters of benzoic acid anddiethylaminoethyl alcohols, namely, benzocaine, chloroprocaine,procaine, and tetracaine. Other synthetic anesthetic compounds, whichare not esters of benzoic acid and are pharmacologically groupedtogether, are bupivacaine, dibucaine, lidocaine, mepivacaine, andprilocaine. Besides these two groups, the compounds of etidocaine andpramoxine are also applicable. In one of the topical spray formulationsdescribed below the anesthetic, pramoxine hydrochloride, comprises up to1.0 percent by weight thereof.

Corticosteroids are a group of agents used to treat inflammation of theskin having many different etiologies. Examples of indications in whichsystemically administered corticosteroids are employed as therapeuticsinclude psoriasis, erythema nodosum leprosum, discold lupuserythematosus, urticaria, different types of pruritis, pemphigus andkeloids. Antihistamines are a group of agents having an antipruriticeffect. They include alkylamines, phenothiazines, ethylenediamine,ethanolamine, and piperazine. Retinoids are synthetic and natural formsof vitamin A, including isotretinoin and etretinate. Retinoids are usedto treat acne vulgaris or rosacea and psoriasis. Antimicrobial compoundsinclude antibiotic, antibacterial, antifungal, antiviral, andantiparasitic agents.

In addition to the imidazole-based compound and colloidal oatmeal, thebenefit agents comprising topical preparations used according to theinvention may also comprise:

-   -   (a) anti pruritic agents, which relieve itching, such as 0.25%        menthol, 0.5% phenol, 2% camphor and 2-10% coal tar solutions;    -   (b) keratoplastic agents, which increase the thickness of the        horny layer of the skin, such as 1-2% salicylic acid;    -   (c) emollients, which often soften surface layers of skin, such        as petrolatum, nivea oil and mineral oil;    -   (d) antiseptics, which inhibit and/or destroy fungi and/or        bacteria, such as 3% Vioform, 3-10% ammoniated mercury,        antifungal agents such as Whitfields ointment, antibiotics such        as 3% terramycin, 0.5% neomycin, 0.1% garamycin and 3%        aureomycin;    -   (e) antieczematous agents, which remove oozing and vesicular        excretions, such as Burows solution, soaks or packs, 2-5% coal        tar solutions and 0.5-2% hydrocortisone;    -   (f) keratolytic agents, which remove or soften the horny layer        of the skin, such as 4-10% salicylic acid, 2-4% resorcinol and        4-10% sulfur; and    -   (g) antiparasitics, which inhibit or destroy infestations by        parasites, such as Kewell cream for scabies and pediculosis and        Eurax lotion for scabies.

Further examples of suitable benefit agents include, but are not limitedto: depigmentation agents; reflectants; film forming polymers;humectants; amino acids and their derivatives;

antimicrobial agents; allergy inhibitors; anti-acne agents; anti-agingagents; anti-wrinkling agents, antiseptics; analgesics; antitussives;antipruritics; local anesthetics; anti-hair loss agents; hair growthpromoting agents; hair growth inhibitor agents, antihistamines such asMandragora Vernalis, Tanacetum Parthenium and the like; antiinfectivessuch as Acacia Catechu, Aloe Barbadensis, Convallaria Maj alis,Echinacea, Eucalyptus, Mentha Piperita, Rosa Canina, Sassafras Albidum,and the like; inflammation inhibitors; anti-emetics; anticholinergics;vasoconstrictors; vasodilators; wound healing promoters; peptides,polypeptides and proteins; deodorants and antiperspirants; medicamentagents; skin emollients and skin moisturizers; skin firming agents, hairconditioners; hair softeners; hair moisturizers; vitamins; tanningagents; skin lightening agents; antifungals such as Centaurea Cyanus,Kalmia Latifolia and antifungals for foot preparations; depilatingagents; shaving preparations; external analgesics; perfumes;counterirritants; hemorrhoidals; insecticides; poison ivy products;poison oak products; burn products; anti-diaper rash agents; pricklyheat agents; make-up preparations; vitamins; amino acids and theirderivatives; herbal extracts; retinoids; flavenoids; sensates;anti-oxidants; skin conditioners; hair tighteners; chelating agents;cell turnover enhancers; coloring agents; pigments; sunscreens;anti-edema agents; collagen enhancers; and mixtures thereof.

Examples of suitable anti-edema agents nonexclusively include bisabololnatural, synthetic bisabolol, and mixtures thereof. Examples of suitablevasoconstrictors nonexclusively include horse chestnut extract, pricklyash, and mixtures thereof. Examples of suitable anti-inflammatory agentsnonexclusively include benoxaprofen, centella asiatica, bisabolol,feverfew (whole), feverfew (parthenolide free), green tea extract, greentea concentrate, hydrogen peroxide, lycopene including “Lyc-o-Pen”available from LycoRed Natural Products Industries, Ltd., oat oil,chamomile, and mixtures thereof. Examples of collagen enhancersnonexclusively include vitamin A, vitamin C, and mixtures thereof.Examples of suitable skin firming agent nonexclusively includedimethylaminoethanol (“DMAE”). Examples of suitable antipruritics andskin protectants nonexclusively include betaglucan, feverfew, soy andderivatives thereof, bicarbonate of soda, colloidal oatmeal, surfactantbased colloidal oatmeal cleanser, Anagallis Arvensis, Oenothera Biennis,Verbena Officinalis, and the like.

Examples of suitable reflectants nonexclusively include mica, alumina,calcium silicate, glycol dioleate, glycol distearate, silica, sodiummagnesium fluorosilicate, and mixtures thereof. Suitable film formingpolymers include those that, upon drying, produce a substantiallycontinuous coating or film on the skin. Nonexclusive examples ofsuitable film forming polymers include acrylamidopropyl trimoniumchloride/acrylamide copolymer; corn starch/acrylamide/sodium acrylatecopolymer; polyquatemium-10; polyquaternium-47;polyvinylmethylether/maleic anhydride copolymer; styrene/acrylatescopolymers; and mixtures thereof. Commercially available humectantswhich are capable of providing moisturization and conditioningproperties to the composition are suitable for use in the presentinvention. Examples of suitable humectants nonexclusively include: watersoluble liquid polyols selected from the group comprising glycerine,propylene glycol, hexylene glycol, butylene glycol, pentylene glycol,dipropylene glycol, and mixtures thereof; polyalkylene glycols;polyethylene glycol ether of methyl glucose; urea; fructose; glucose;honey; lactic acid; maltose; sodium glucuronate; and mixtures thereof.

Suitable amino acid agents include amino acids derived from thehydrolysis of various proteins as well as the salts, esters, and acylderivatives thereof. Examples of such amino acid agents nonexclusivelyinclude amphoteric amino acids such as alkylamido alkylamines, i.e.stearyl acetyl glutamate, capryloyl silk amino acid, capryloyl collagenamino acids; capryloyl keratin amino acids; capryloyl pea amino acids;cocodimonium hydroxypropyl silk amino acids; corn gluten amino acids;cysteine; glutamic acid; glycine; hair keratin amino acids; amino acidssuch as aspartic acid, threonine, serine, glutamic acid, proline,glycine, alanine, cystine, valine, methionine, isoleucine, leucine,tyrosine, phenylalanine, cysteic acid, lysine, histidine, arginine,cysteine, tryptophan, citrulline; lysine; silk amino acids, wheat aminoacids; and mixtures thereof.

Suitable proteins include those polymers that have a long chain, i.e. atleast about 10 carbon atoms, and a high molecular weight, i.e. at leastabout 1000, and are formed by self-condensation of amino acids.Nonexclusive examples of such proteins include collagen,deoxyribonuclease, iodized corn protein; milk protein; protease; serumprotein; silk; sweet almond protein; wheat germ protein; wheat protein;alpha and beta helix of keratin proteins; hair proteins, such asintermediate filament proteins, high-sulfur proteins, ultrahigh-sulfurproteins, intermediate filament-associated proteins, high-tyrosineproteins, high-glycine tyrosine proteins, tricohyalin, and mixturesthereof.

Examples of suitable vitamins nonexclusively include vitamin B complex;including thiamine, nicotinic acid, biotin, pantothenic acid, choline,riboflavin, vitamin B6, vitamin B12, pyridoxine, inositol, carnitine;vitamins A, C, D, E, K and their derivatives such as vitamin A palmitateand pro-vitamins, e.g. (i.e. panthenol (pro vitamin B5) and panthenoltriacetate) and mixtures thereof.

Examples of suitable antibacterial agents nonexclusively includebacitracin, erythromycin, neomycin, tetracycline, chlortetracycline,benzethonium chloride, phenol, and mixtures thereof.

Examples of suitable skin emollients and skin moisturizersnonexclusively include mineral oil, lanolin, vegetable oils, isostearylisostearate, glyceryl laurate, methyl gluceth-10, methyl gluceth-20chitosan, and mixtures thereof.

Examples of sunscreen agents nonexclusively include benzophenones,bornelone, butyl paba, cinnamidopropyl trimethyl ammonium chloride,disodium distyrylbiphenyl disulfonate, paba, potassium methoxycinnamate,butyl methoxydibenzoylmethane, octyl methoxycinnamate, oxybenzone,octocrylene, octyl salicylate, phenylbenzimidazole sulfonic acid, ethylhydroxypropyl aminobenzoate, menthyl anthranilate, aminobenzoic acid,cinoxate, diethanolamine methoxycinnamate, glyceryl aminobenzoate,titanium dioxide, zinc oxide, oxybenzone, Padimate O, red petrolatum,and mixtures thereof. Further examples of sunscreen active agentsinclude, but are not limited to octyl methoxycinnamate (ethylhexylp-methoxycinnamate), octyl salicylate oxybenzone (benzophenone-3),benzophenone-4, menthyl anthranilate, dioxybenzone, aminobenzoic acid,amyl dimethyl PABA, diethanolamine p-methoxy cinnamate, ethyl 4-bis(hydroxypropyl) aminobenzoate, 2-ethylhexy1-2-cyano-3,3-diphenylacrylate, homomenthyl salicylate, glycerylaminobenzoate, dihydroxyacetone, octyl dimethyl PABA,2-phenylbenzimidazole-5-sulfonic acid, triethanolamine salicylate, zincoxide, and titanium oxide, and mixtures thereof.

Examples of suitable anti-aging agents include, but are not limited toinorganic sunscreens such as titanium dioxide and zinc oxide; organicsunscreens such as octyl-methoxy cinnamates and derivatives thereof;retinoids; vitamins such as vitamin E, vitamin A, vitamin C, vitamin B,and derivatives thereof such as vitamin E acetate, vitamin C palmitate,and the like; antioxidants including beta carotene, alpha hydroxy acidssuch as glycolic acid, citric acid, lactic acid, malic acid, mandelicacid, ascorbic acid, alpha-hydroxybutyric acid, alpha-hydroxyisobutyricacid, alpha-hydroxyisocaproic acid, atrrolactic acid,alpha-hydroxyisovaleric acid, ethyl pyruvate, galacturonic acid,glucoheptonic acid, glucoheptono 1,4-lactone, gluconic acid,gluconolactone, glucuronic acid, glucuronolactone, glycolic acid,isopropyl pyruvate, methyl pyruvate, mucic acid, pyruvic acid, saccharicacid, saccaric acid 1,4-lactone, tartaric acid, and tartronic acid; betahydroxy acids such as beta-hydroxybutyric acid, beta-phenyl-lactic acid,beta-phenylpyruvic acid; botanical extracts such as green tea, soy, milkthistle, algae, aloe, angelica, bitter orange, coffee, goldthread,grapefruit, hoellen, honeysuckle, Job's tears, lithospermum, mulberry,peony, puerarua, nice, safflower, and mixtures thereof.

Examples of suitable external analgesics and local anestheticsnonexclusively include benzocaine, dibucaine, benzyl alcohol, camphor,capsaicin, capsicum, capsicum oleoresin, juniper tar, menthol, methylnicotinate, methyl salicylate, phenol, resorcinol, turpentine oil, andmixtures thereof.

Examples of suitable antiperspirants and deodorants nonexclusivelyinclude aluminium chlorohydrates, aluminium zirconium chlorohydrates,and mixtures thereof.

Examples of suitable counterirritants nonexclusively include camphor,menthol, methyl salicylate, peppermint and clove oils, ichtammol, andmixtures thereof. Examples of suitable inflammation inhibitorsnonexclusively includes hydrocortisone, Fragaria Vesca, MatricariaChamomilla, and Salvia Officinalis. Other well-known antipruritic agentsinclude phenol, camphor, menthol, hydro-cortisone, hydrocortisoneacetate, camphorated metacresol, phenolated sodium, and mixturesthereof.

Other preferred benefit agents nonexclusively include DMAE, soy andderivatives thereof, colloidal oatmeal, sulfonated shale oil, oliveleaf, elubiol, 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide,finasteride, ketoconazole, salicylic acid, zinc pyrithione, coal tar,benzoyl peroxide, selenium sulfide, hydrocortisone, sulfur, menthol,pramoxine hydrochloride, tricetylmonium chloride, polyquaternium 10,panthenol, panthenol triacetate, vitamin A and derivatives thereof,vitamin B and derivatives thereof, vitamin C and derivatives thereof,vitamin D and derivatives thereof, vitamin E and derivatives thereof,vitamin K and derivatives thereof, keratin, lysine, arginine, hydrolyzedwheat proteins, hydrolyzed silk proteins, octyl methoxycinnamate,oxybenzone, minoxidil, titanium dioxide, zinc dioxide, retinol,erthromycin, tretinoin, and mixtures thereof.

One preferred type of benefit agent includes those therapeuticcomponents that are effective in the treatment of seborrheic dermatitisand psoriasis as well as the symptoms associated therewith. Examples ofsuch suitable benefits agents nonexclusively include zinc pyrithione,anthralin, shale oil and derivatives thereof such as sulfonated shaleoil, selenium sulfide, sulfur; salicylic acid; coal tar;povidone-iodine, imidazoles such as ketoconazole, dichlorophenylimidazolodioxalan, which is commercially available from JanssenPharmaceutica, Nev., under the tradename, “Elubiol”, clotrimazole,itraconazole, miconazole, climbazole, tioconazole, sulconazole,butoconazole, fluconazole, miconazole nitrate and any possible stereoisomers and derivatives thereof; piroctone olamine (Octopirox); seleniumsulfide; ciclopirox olamine; anti-psoriasis agents such as vitamin Danalogs, e.g. calcipotriol, calcitriol, and tacaleitrol; vitamin Aanalogs such as esters of vitamin A, e.g. vitamin A palmitate,retinoids, retinols, and retinoic acid; corticosteroids such ashydrocortisone, clobetasone, butyrate, clobetasol propionate andmixtures thereof.

Further examples of benefit agents are emollients, skin conditioningagents, humectants, preservatives, antioxidants, perfumes, chelatingagents, or mixtures thereof. Emollients in the composition of theinvention function have ability to remain on the skin surface or in thestratum corneum to act as lubricants, to reduce flaking, and to improvethe skin appearance. Typical emollients include fatty esters, fattyalcohols, mineral oil, polyether siloxane copolymers and the like.Examples of suitable emollients include, but are not limited to,polypropylene glycol (“PPG”)-15 stearyl ether, PPG-10 acetyl ether,steareth-10, oleth-8, PPG-4 lauryl ether, vitamin E acetate, PEG-7glyceryl cocoate, lanolin, cetyl alcohol, (e.g., Cetyl Alcohol NFavailable from Lotioncrafter LLC) octyl hydroxystearate, dimethicone(e.g., Xiameter® PMX-200 Silicone Fluid 100CS available from DowCorning), and combinations thereof.

Examples of skin conditioning agents include, but are not limited to,olive leaf, sulfonated shale oil, elubiol,6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, finasteride,ketoconazole, zinc pyrithione, coal tar, benzoyl peroxide, seleniumsulfide, hydrocortisone, pramoxine hydrochloride, tricetylammoniumchloride, polyquaternium 10, panthenol, panthenol triacetate, vitamin Band derivatives thereof, vitamin C and derivatives thereof, vitamin Dand derivatives thereof, vitamin E and derivatives thereof, vitamin Kand derivatives thereof, keratin, lysine, arginine, hydrolyzed wheatproteins, hydrolyzed silk proteins, octyl methoxycinnamate, oxybenzone,minoxidil, titanium dioxide, zinc dioxide, erthromycin, tretinoin, andmixtures thereof.

Polyhydric alcohols can be utilized as humectants in the compositions ofthe invention. The humectants aid in increasing the effectiveness of theemollient, reduce scaling, stimulate removal of built-up scale andimprove skin feel. Suitable polyhydric alcohols include, but are notlimited to, glycerol (also known as glycerin), polyalkylene glycols,alkylene polyols and their derivatives, including butylene glycol,propylene glycol, dipropylene glycol, polypropylene glycol, polyethyleneglycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol,hexylene glycol, 1,3-dibutylene glycol, 1,2,6,-hexanetriol, ethoxylatedglycerol, propoxylated glycerol and mixtures thereof.

Examples of suitable preservatives for use in the compositions of theinvention include the C₁-C₄ alkyl parabens and phenoxyethanol (e.g.,Microcare® PE available from Thor Personal Care). Suitable antioxidantsinclude butylated hydroxy toluene (BHT), ascorbyl palmitate, butylatedhydroanisole (BHA), phenyl-[alpha]-naphthylamine, hydroquinone, propylgallate, nordihydroquiaretic acid, vitamin E or derivatives of vitaminE, vitamin C and derivatives thereof, calcium pantothenic, green teaextracts and mixed polyphenols, and mixtures thereof. Any fragrance maybe added to the compositions of the invention for aesthetic purposes.Suitable fragrances include, but are not limited to, eucalyptus oil,camphor synthetic, peppermint oil, clove oil, lavender, chamomile andthe like.

In certain aspects of this invention, the compositions may include achelating agent. Chelating agents which are useful in the compositionsof present invention include ethylenediamine tetra acetic acid (EDTA)and derivatives and salts thereof, dihydroxyethyl glycine, tartaricacid, and mixtures thereof.

It is also envisioned that the composition of this invention could becombined with other agents topical anesthetics, for example, such asbenzocaine or other caine type molecules, or even mild steroids such ashydrocortisone for enhanced anti-inflammatory activity.

Further benefit agents useful in the compositions and methods of thepresent invention include, but are not limited to:

-   -   antihistamine/antipruritic drugs, such as ethanolamines (e.g.,        diphenhydramine, diphenhydramine hydrochloride, clemastine,        clemastine fumarate, and the like), ethylenediamines (e.g.,        brompheniramine, brompheniramine maleate, chlorpheniramine,        chlorpheniramine maleate, dexchlorpheniramine maleate,        triprolidine, triprolidine hydrochloride, and the like),        phenothiazines (e.g., promethazine), piperidines (e.g.,        hydroxzine, hydroxyzine hydrochloride, terfenadine, astemizole,        azatadine, azatadine maleate, and the like), cyproheptadine,        cyproheptadine hydrochloride, loratidine, carbinoxamine maleate,        diphenylpyraline hydrochloride, phenindamine tartrate,        tripelennamine hydrochloride, methdilazine hydrochloride,        trimprazine tartrate, and the like;    -   immunosuppressants, such as glucocorticoids        (methylprednisolone), myelin basic protein (e.g., 7-capaxone),        anti-Fe receptor monoclonal antibodies, hydroorotate        dehydrogenase inhibitor, anti-IL2 monoclonal antibodies (e.g.,        CHI-621 and dacliximab), buspirone, castanospermine, CD-59        (complement factor inhibitor), 5-lipoxygenase inhibitor (e.g.,        CMI-392), phosphatidic acid synthesis antagonists, ebselen,        edelfosine, enlimomab, galaptin, platelet activating factor        antagonists, selectin antagonists (e.g., ICAM-4), interleukin-10        agonist, macrocylic lactone, methoxatone, mizoribine, OX-19,        peptigen agents, PG-27, protein kinase C inhibitors,        phosphodiesterase IV inhibitor, single chain antigen binding        proteins, complement factor inhibitor, sialophorin, sirolimus,        spirocyclic lactams, 5-hydroxytryptamine antagonist, anti-TCR        monoclonal antibodies, CD5 gelonin and TOK-8801, and the like;    -   antibacterial agents (e.g., amikacin sulfate, aztreonam,        chloramphenicol, chloramphenicol palmitate, chloramphenicol        sodium succinate, ciprofloxacin hydrochloride, clindamycin        hydrochloride, clindamycin palmitate, clindamycin phosphate,        metronidazole, metronidazole hydrochloride, gentamicin sulfate,        lincomycin hydrochloride, tobramycin sulfate, vancomycin        hydrochloride, polymyxin B sulfate, colistimethate sodium,        colistin sulfate, and the like);    -   antifungal agents (e.g., griseofulvin, keloconazole, and the        like); antiviral agents (e.g., interferon gamma, zidovudine,        amantadine hydrochloride, ribavirin, acyclovir, and the like);    -   antimicrobials (e.g., cephalosporins (e.g., cefazolin sodium,        cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium,        cefoperazone sodium, cefotetan disodium, cefutoxime azotil,        cefotaxime sodium, cefadroxil monohydrate, ceftazidime,        cephalexin, cephalothin sodium, cephalexin hydrochloride        monohydrate, cefamandole nafate, cefoxitin sodium, cefonicid        sodium, ceforanide, ceftriaxone sodium, ceftazidime, cefadroxil,        cephradine, cefuroxime sodium, and the like), penicillins (e.g.,        ampicillin, amoxicillin, penicillin G benzathine, cyclacillin,        ampicillin sodium, penicillin G potassium, penicillin V        potassium, piperacillin sodium, oxacillin sodium, bacampicillin        hydrochloride, cloxacillin sodium, ticarcillin disodium,        azlocillin sodium, carbenicillin indanyl sodium, penicillin G        potassium, penicillin G procaine, methicillin sodium, nafcillin        sodium, and the like), erythromycins (e.g., erythromycin        ethylsuccinate, erythromycin, erythromycin estolate,        erythromycin lactobionate, erythromycin siearate, erythromycin        ethylsuccinate, and the like), tetracyclines (e.g., tetracycline        hydrochloride, doxycycline hyclate, minocycline hydrochloride,        and the like), and the like);    -   antioxidants (e.g., N-acetylcsysteine, Vitamin A, Vitamin C,        Vitamin E, .beta.-carotene, EUK-8, flavonoids, glutathione,        .alpha.lipoic acid, melatonin, retinols, and the like);        anti-infectives (e.g., miconazole, vidarabine, inosine,        pranobex, vidarabine, inosine prabonex, cefpimizole sodium),        fradiomycin, and the like);    -   hormones (e.g., androgens (e.g., danazol, testosterone        cypionate, fluoxymesterone, ethyltostosterone, testosterone        enanihate, methyltestosterone, fluoxymesterone, testosterone        cypionate), estrogens (e.g., estradiol, estropipate, conjugated        estrogens), progestins (e.g., methoxyprogesterone acetate,        norethindrone acetate), corticosteroids (e.g., triamcinolone,        betamethasone, betamethasone sodium phosphate, dexamethasone,        dexamethasone sodium phosphate, dexamethasone acetate,        prednisone, methylprednisolone acetate suspension, triamcinolone        acetonide, methylprednisolone, prednisolone sodium phosphate        methylprednisolone sodium succinate, hydrocortisone sodium        succinate, methylprednisolone sodium succinate, triamcinolone        hexacatonide, hydrocortisone, hydrocortisone cypionate,        prednisolone, fluorocortisone acetate, paramethasone acetate,        prednisolone tebulate, prednisolone acetate, prednisolone sodium        phosphate, hydrocortisone sodium succinate, and the like),        thyroid hormones (e.g., levothyroxine sodium) and the like), and        the like;    -   psoriasis agents, such as 5-LO inhibitors (e.g., Wy-50295,        Wy-49232, Lonapalene, RS-43179, MK-886, L-663536, ETH-615,        DUP-654, Zileuton, epocarbazolin-A, and A-64077), 5-LO/CO        inhibitors (e.g., BF-397, Tenidap, CP-309, and CP-66248),        angiogenesis inhibitors (e.g., platelet factor 4), anticancer        antibiotic (e.g., AGM-1470, and TNP-470), anti-inflammatory        cytochrome P450 oxidoreductase inhibitors (e.g., DuP-630, and        DuP-983), antiproliferative compounds (e.g., Zyn-Linker),        arachidonic acid analogues (e.g., CD581, and CD554), arachidonic        acid antagonists (e.g., Lonopalene, RS-43179, triamcinolone        acetonide with penetration enhancer Azone, betamethasone        dipropionate steroid wipe, G-202, Halobetasol propionate,        ultravate, Halometasone, C-48401-Ba, and Sicorten), beta-glucan        receptor antagonists, betamethasone steroid wipes, calcium        metabolic moderators (e.g., Tacalcitol, Bonealfa, TV-02        ointment, Ro-23-6474, KH-1060, Calcipotriol, BMS-181161,        BMY-30434, Dovonex, and Divonex), CD4 binding inhibitors (e.g.,        PIC 060), cell adhesion compounds (e.g., CY-726, VCAM-1, ELAM-1,        and ICAM), cell adhesion inhibitors (e.g., selectin inhibitor,        GM-1930), cellular aging inhibitors (e.g., Factor X),        corticosteroids (e.g., Halobetasol propionate, ultravate,        Halometasone, C-48401-Ba, and Sicorten), cyclosporin analogues        (e.g., IMM-125), dihydrofolate reductase inhibitors (e.g.,        G-301, dichlorobenzoprim, methotrexate, and methotrexate in        microsponge delivery system), E-selectin inhibitors (e.g., ISIS        4730), endogenous active form of vitamin D3 (e.g., Calcitriol,        and Du-026325), fibroblast growth factor antagonists (e.g.,        Saporin mitotoxin, and Steno-Stat), fumagillin analogues (e.g.,        AGM-1470, and TNP-470), G-proteins and signal transduction        compounds (e.g., CPC-A), gel formulations for acne (e.g.,        nicotinamide, N-547, and Papulex), growth hormone antagonists        (e.g., Octreotide, Sandostatin, Lanreotide, angiopeptin,        BIM-23014, and Somatuline), humanized antibodies (e.g., anti-CD4        antibody), hydroorotate dehydrogenase inhibitors (e.g.,        Brequinar sodium, bipenquinate, and DuP-785), ICAM-1 inhibitors        (e.g., ISIS 939), IL-1 and other cytokine inhibitors (e.g.,        Septanil), IL-1 converting ezyme inhibitors, IL-1 receptor        antagonists (e.g., Antril), IL-2 antagonists (e.g., Tacrolimus,        Prograf, and FK-506), IL-2 receptor-targeted fusion toxins        (DAB389IL-2), IL-8 receptors, immunostimulants (e.g.,        Thymopentin, and Timunox), immunosuppressants (e.g.,        XomaZyme-CD5 Plus, cyclosporine, Sandimmune, SR-31747, anti-CD        11, 18 MAb, Tacrolimus, Prograf, FK-506, and FK-507),        immunosuppressive agents targeting FK506 (e.g., immunophilins,        VX-10367, and VX-10428), immunotoxins MAb directed against CD        antigen (e.g., XomaZyme-CD5 Plus), leukotriene antagonists        (e.g., Sch-40120, Wy-50295, and Wy49232), leukotriene B4        antagonists (e.g., SC-41930, SC-50605, SC-48928, ONO-4057,        LB-457, LY-255283, LY-177455, LY-223982, LY-223980, and        LY-255253), leukotriene synthesis inhibitors (MK-886, and        L-663536), lipase clearing factor inhibitors (e.g., 1-docosanol,        and lidakol), lipid encapsulated reducing agent (e.g.,        Dithranol), liposomal gel (e.g., Dithranol), LO inhibitors        (e.g., CD581, CD554, Masoprocol, and Actinex), lithium succinate        ointments (e.g., lithium salts, and Efalith), LO/CO inhibitors        (e.g., P-8892, P-8977, CHX-108, and FPL-62064), membrane        integrity agonists (e.g., lithium salts, and Efalith),        microtubule inhibitors (e.g., Posophyliotoxin-containing        compound, and Psorex), octapeptide somatostatin analogues (e.g.,        Lanreotide, angiopeptin, BIM-23014, and Somatuline),        oligonucleotides (e.g., ISIS 4730, ISIS 3801, ISIS 1939, and        IL-1 inhibitors), peptide agonists (e.g., octapeptide, and        peptide T), PKC inhibitors, phospholipase A2 compounds,        pospholipase D compounds, photodynamic anticancer agents (e.g.,        5-aminolevulinic acid, and 5-ALA), photodynamic therapies (e.g.,        benzoporphyrin derivative, synthetic chlorins, synthetic        porphyrins, and EF-9), photosensitizer (e.g., Porfirmer sodium),        PKC inhibitors (e.g., Safingol, and Kynac), platelet activating        factor antagonists (e.g., TCV-309), platelet aggregation        inhibitors (e.g., CPC-A), prodrug NSAIDs (e.g., G-201),        prostaglandin agonist (e.g., eicosapentaenoic acid        +gamma-linolenic acid combination, and Efamol Marine), protein        inhibitors (e.g., SPC-103600, and SPC-101210), protein kinase C        (PKC) inhibitors (e.g., Ro-31-7549, Ro-31-8161, and Ro-31-8220),        protein synthesis antagonists (e.g., Calcitriol, Du-026325,        LG-1069, LG-1064, AGN-190168, Namirotene, and CBS-211A), purine        nucleoside phosphorylase inhibitors (e.g., BCX-34), radical        formation agonists (e.g., benzoporphyrin derivative),        recombinant antileukoproteinases (e.g., ALP-242), retinoids        (e.g., BMY-30123, LG-1Q69, and LG-1064), retinoid derivatives        (e.g., AGN-190168), rapamycin binding proteins (FKBP) (e.g.,        immunophilins, VX-10367, and VX-10428), second generation        monoaromatic retinoids (e.g., Acitretin, and Neotigason),        soluble IL-1, IL-4 and IL-7 receptors, somatostatin and        somatostatin analogues (e.g., Octreotide, and Sandostatin),        steroids, (e.g., AGN-191743), streptomyces anulatus isolates        (e.g., epocarbazolin-A), superoxide dismutase (e.g., EC-SOD-B),        thymidylate synthase inhibitors (e.g., AG-85, MPI-5002, 5-FU in        biodegradable gel-like matrix, 5-FU and epinephrine in        biodegradable gel-like matrix, and AccuSite), topical        formulations (e.g., P-0751, and P-0802), transglutaminase        inhibitors, tyrphostin EGF receptor kinase blockers (e.g.,        AG-18, and AG-555), VCAM-1 inhibitors (e.g., ISIS 3801), vitamin        D analogues (e.g., Ro-23-6474, KH-1060, Calcipotriol,        BMS-181161, BMY-30434, Dovonex, and Divonex), vitamin D3        analogues (e.g., Tacalcitol, 20 Bonealfa, TV-02 ointment), and        vitamin D3 derivatives (e.g., 1,2-diOH-vitamin D3), and the        like; and    -   agents useful for the treatment of carcinomas (e.g., adriamycin,        taxol, interleukin-1, interleukin-2 (especially useful for        treatment of renal carcinoma), and the like, as well as        leuprolide acetate, LHRH analogs (such as nafarelin acetate),        and the like, which are especially useful for the treatment of        prostatic carcinoma).

The amount of benefit agent to be included may vary depending upon, forexample, the ability of the benefit agent to penetrate through the skin,the specific benefit agent chosen, the particular benefit desired, thesensitivity of the user to the benefit agent, the health condition, age,and skin condition of the user, and the like. In sum, the benefit agentis used in a “safe and effective amount,” which is an amount that ishigh enough to deliver a desired skin benefit or to modify a certaincondition to be treated, but is low enough to avoid serious sideeffects, at a reasonable risk to benefit ratio within the scope of soundmedical judgment.

Formulations

The compositions of the present invention can be prepared andadministered in a wide variety of topical forms. For topicalformulations of the present invention, dermatologically acceptablecarriers can be either solid or liquid. The compositions of thisinvention is preferably in the form of topical products that can beapplied externally to the skin and can be prepared in accordance withconventional techniques known to those of ordinary skill in the art. Thecarrier may take a variety of physical forms such as, for example,creams, dressings, gels, lotions, ointments or liquids. One could alsoutilize this in a convenient spray applicator.

Typical carriers include lotions containing water and/or alcohols andemollients such as hydrocarbon oils and waxes, silicone oils, hyaluronicacid, vegetable, animal or marine fats or oils, glyceride derivatives,fatty acids or fatty acid esters or alcohols or alcohol ethers, lanolinand derivatives, polyhydric alcohols or esters, wax esters, sterols,phospholipids and the like, and generally also emulsifiers (nonionic,cationic or anionic), although some of the emollients inherently possessemulsifying properties. These same general ingredients can be formulatedinto a cream rather than a lotion, or into gels, or into solid sticks byutilization of different proportions of the ingredients and/or byinclusion of thickening agents such as gums or other forms ofhydrophillic colloids.

The compositions according to the invention preferably contain aneffective stabilizing amount of an emulsifier. Any emulsifier that iscompatible with the components of the composition can be employed.Suitable emulsifiers include stearic acid, acetyl alcohol, stearylalcohol, steareth 2, steareth 20, Acrylates/C10-30 alkyl AcrylateCrosspolymer Particularly preferred is PEMULEN TR-1 (CTFA Designation:Acrylates/10-30 Alkyl Acrylate Crosspolymer).

The composition of the invention may be in the form of an oil-in-wateremulsion, a water-in-oil emulsion, or a dispersion. Liquid formpreparations such as lotions or creams include solutions, suspensions,and emulsions, for example, water or DMSO/propylene glycol solutions.Liquid suspensions suitable for topical use can be made by dispersingthe finely divided active component in an appropriate liquid withviscous material, such as natural or synthetic gums, resins,methycellulose, sodium carboxymethylcellulose, and other well-knownsuspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for topicaladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, addition to the activecomponent, colorants, flavors, fragrances, stabilizers, buffers,artificial and natural sweeteners, dispersants, thickeners, solubilizingagents, and the like.

To prepare dermally applicable formulations it is possible to use thepreviously mentioned substances and spreadable or liquid hydrocarbonssuch as Vaseline or paraffin or gels of alkanes and polyethylene, fatsand oils of plant or animal origin, which may in part also be hydrated,or synthetic fats such as glycerides of fatty acids C₈-C₁₈, as well asbeeswax, cetyl palmitate (e.g., Cutina® CP available from Cognis/BASF),wool wax, wool wax alcohols, fatty alcohols such as cetyl alcohol,stearyl alcohol, polyethylene glycols of molecular weight 200 to 20,000;liquid waxes such as isopropyl myristate, isopropyl stearate,ethyloleate; emulsifiers such as sodium, potassium, ammonium salts ofstearic acid or palmitic acid as well as triethalolamine stearate,alkali salts of oleic acid, castor oil acid, salts of sulfurated fattyalcohols such as sodium lauryl sulphate, sodium cetyl sulphate, sodiumstearyl sulphate, salts of gallic acid, sterols such as cholesterol,partial fatty acid esters of multivalent alcohols such as ethyleneglycol monostearate, glycerol monostearate, pentaerythritolmonostearate, partial fatty acid esters of sorbitan, partial fatty acidesters of polyoxyethylene sorbitan, sorbitol ethers of polyoxyethylene,fatty acid esters of polyoxyethylene, fatty alcohol ethers ofpolyoxyethylene, fatty acid esters of saccharose, fatty acid esters ofpolyglycerol, lecithin.

Examples of suitable esters nonexclusively include a branched C₅ to C₂₂alkyl alcohol ester of an aromatic acid, a straight-chained or branchedC₅ to C₂₂ alkyl acid esters of optionally ethyoxylated/propoxylatedpolyols having from about 3 carbon atoms to about 7 carbon atoms, abranched C₅ to C₂₂ alkyl alcohol esters of branched polyacids, abranched or straight-chained C₅ to C₂₂ alkyl acid esters of branchedand/or unsaturated C₅ to C₂₂ alkyl alcohols, a branched or unsaturatedC₅ to C₂₂ alkyl alcohol esters of an acid selected from the groupconsisting of adipic acid, succinic acid, maleic acid, sebacic acid, andmixtures thereof, polyether interrupted fatty acid esters, benzoic acidester of heterogeneous alcohols having from about 8 carbon atoms toabout 22 carbon atoms and mixtures thereof with straight-chained orbranched C₅ to C₂₂ alkyl acid esters of optionallyethyoxylated/propoxylated polyols, benzoic acid esters of heterogeneousalcohols, and mixtures thereof. Further suitable esters are disclosed inU.S. Pat. No. 6,762,158, the entire disclosure of which is incorporatedherein by reference.

Antioxidants that may for example be used are sodium metabisulphite,ascorbic acid, gallic acid, gallic acid alkyl ester, butylhydroxyanisol,nordihydroguaiacic acid, tocopherols as well as tocopherols.+-.synergitic substances that bind heavy metals through complexformation, for example lecithin, ascorbic acid, phosphoric acid).Conserving agents that may for example be considered are sorbic acid,p-hydroxybenzoic acid esters (for example lower alkyl esters), benzoicacid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol,benzethonium chloride and formalin derivatives.

Topical dosage forms include, but are not limited to, sprays, aerosols,creams, lotions, ointments, gels, solutions, emulsions, suspensions, orother forms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). See also Cosmetic Model Formulae—ACompilation of Model Formulae for the Manufacture of CosmeticPreparations (Henkel KGaA; 1988), the entirety of which is incorporatedherein by reference. Transdermal dosage forms include “reservoir type”or “matrix type” patches, which can be applied to the skin and worn fora specific period of time to permit the penetration of a desired amountof active ingredients. Suitable excipients (e.g., carriers and diluents)and other materials that can be used to provide transdermal, topical,and mucosal dosage forms are well known to those skilled in thepharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied.

The pH of the inventive compositions may also be adjusted to improvedelivery of one or more active ingredients. In another preferredembodiment, the compositions used in the methods of present inventioncontain a pH-buffering agent. Preferably, the amount of buffering agentshould be that which would result in compositions having a pH rangingfrom about 4.5 to about 8:5, more preferably from about 5.5 to about8.5, most preferably from about 6.5 to about 8.0. The buffering agentcan be any of the known buffering agents commonly found in topicalcompositions provided that they are physically and chemically stablewith the other ingredients of the composition. Suitable buffering agentsinclude organic acids such as, but not intended to be restricted to,citric acid, malic acid, and glycolic acid.

Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates may also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

The topical compositions of the present invention may contain a waterdispersible component, which is preferably a water soluble solvent. Asused herein, the term “water dispersible component” shall mean amaterial that produces a uniform, clear or hazy, mixture when combinedwith at least a weight equivalent of water. Examples of suitable waterdispersible components nonexclusively include polyethylene glycol 400,hexylene glycol, propylene glycol, polypropylene glycol-10 methylglucoseether, ethoxydiglycol, polyethylene glycol-6 caprylic/capric glyceride,ethylene glycol monobutyl ether, polyethylene glycol-8 caprylic/capricglycerides, 3-methoxy-3-methyl-1-butanol, dimethyl isosorbide, andmixtures thereof. Most preferred water dispersible components includehexylene glycol, dimethyl isosorbide, polyethylene glycol-6caprylic/capric glyceride, and mixtures thereof.

A further optional component of the compositions of the presentinvention is a volatile or nonvolatile liquid silicone. Examples ofsuitable silicones nonexclusively include the polydimethyl siloxanes andderivatives thereof such as hexamethylsiloxane, dimethicone,dimethiconol, and cyclomethicone, with cyclomethicone being preferred.Examples of suitable cyclomethicones nonexclusively includecyclotetradimethyl siloxane; cyclopentadimethyl siloxane,cyclohexadimethyl siloxane, cycloheptadimethyl siloxane, and mixturesthereof.

Further optional components of the compositions of the present inventionare polymeric emulsifiers and/or thickeners. Examples of suitablepolymeric emulsifiers nonexclusively include polyethylene glycol-30dipolyhydroxystearate, dimethicone copolyol, substituted acrylates, andmixtures thereof. Examples of suitable hydrophilic thickenersnonexclusively include carbomers (e.g., Carbopol® Ultrez polymersavailable from Lubrizol Corp.; also various carbomer prodcts availablefrom B. F. Goodrich), acrylate copolymers, hydroxyethylcellulosemodified with cetyl ether groups, polyvinylmethyl ether/maleic anhydride(PVM/MA) decadiene crosspolymer, and copolymers and mixtures thereof.Examples of suitable acrylate copolymers nonexclusively include acrylatecopolymers available from Rohm & Haas, acrylates/aminoacrylatescopolymer, acrylates/steareth-20 itaconate copolymer,acrylates/ceteth-20 itaconate copolymer, acrylates/steareth-20methacrylate copolymer, and copolymers and mixtures thereof.

The compositions of the present invention may also optionally contain astability enhancer for the purpose of enhancing the stability of thebenefit agent and/or the aesthetics of the composition. Generally, thestability enhancer may be selected from a nonionic emulsifier, anessentially non-foaming surfactant, or mixtures thereof. Examples ofsuitable nonionic emulsifiers include isocetheth-20, oleth-2, mixture ofPEG-40 hydrogenated castor oil and trideceth-9, Poloxamer 184,laureth-4, sorbitan trioleate, polyoxyethylene-(2) oleyl ether, sorbitanstearate, cetearyl glucoside, glyceryl oleate, trideceth-9, polyethyleneglycol-40 hydrogenated castor oil, and mixtures thereof.

Examples of suitable essentially non-foaming surfactants includenon-foaming nonionic surfactants such as sucrose esters, e.g., sucrosecocoate, sucrose stearate and mixtures thereof. By “essentiallynon-foaming,” it is meant that the surfactant, when used with thecomposition of the present invention, has a column height of less thanabout 20 mm as determined by the Ross-Miles Foam Generation Test. See 18(I.) Oil & Soap 99-102 (1941)(“Ross-Miles Test”), which is incorporatedby reference herein. The composition may either be rinseable with wateror may be wiped-off. Preferably, the essentially non-foaming surfactantsare used in embodiments wherein the composition is rinseable with water.

The composition may also optionally contain a foaming surfactant. Thefoaming surfactant may be non-ionic, cationic, amphoteric, or anionic.By “foaming,” it is meant that the surfactant, when used with thecomposition of the present invention, has a column height of foamgreater than about 20 mm as determined by the Ross-Miles Test.

Preservatives for the formulations herein are benzoic acid andderivatives thereof, namely, butylparaben, ethylparaben, methylparaben,propylparaben, sodium benzoate, and mixtures thereof. Typical use ofbenzoic-acid-derived preservative is a mixture of methylparabencomprising up to 0.3 percent by weight of the treating composition andpropylparaben comprising up to 0.1 percent by weight of the treatingcomposition. Other useful preservatives include alcohol, benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,chlorhexidine, chlorobutanol, chlorocresol, cresol, glycerin, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate,phenylmercuric borate, phenylmercuric nitrate, potassium sorbate,propylene glycol, sodium propionate, sorbic acid and thimerosal.

Among the inactive ingredients are surfactants and emulsifying agents.These ingredients take on importance as the use thereof improvesabsorption, coverage, appearance, and feel of the product. Some suitableemulsifying agents are acacia, anionic emulsifying wax, carbomer,carboxymethyl cellulose, cetostearyl alcohol, cetyl alcohol,cholesterol, diethanolamine, glyceryl monostearate, hydrous lanolin,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lanolin, lanolin alcohols, lecithin, methylcellulose,mineral oil and lanolin alcohols, monobasic sodium phosphate,monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer,polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates,propylene glycol alginate, sodium lauryl sulfate, sorbitan esters,stearic acid, triethanolamine, and xanthan gum. Frequently mixtures ofcomplimentary surfactants are used in a given formulation.

Suitable anionic surfactants are lauryl sulfates, including sodiumlauryl sulfate, triethanolamine lauryl sulfate, and ammonium laurylsulfate; laureth sulfates,including sodium laureth sulfate,triethanolamine laureth sulfate, and ammonium laureth sulfate;sarcosines, including lauryl sarcosine, and sodium lauryl sarcosinate;sulfosuccinates, including disodium oleamine sulfosuccinate, and sodiumdioctyl sulfosuccinate; and docusate sodium. The cationic surfactantsare benzalkonium chloride, benzethonium chloride, and cetrimide. Thenonionic surfactants are glyceryl monooleate, polyvinyl alcohol,sorbitan esters, povidone, crospovidone, polyoxyethylene fatty alcohols,polyoxyethylene sorbitol esters, and alkanolamides. Additionally,amphoteric detergents such as betaines, sultaines, and imidazoliniumderivatives are used, and particularly ingredients such ascocamidopropyl betaine and sodium lauraminopropionate.

In ointment and cream preparations, emollients form a vehicle to carrythe active ingredients to the site of the immune response and theassociated dermatitis. The emollient group from which these carriers areselected include allantoin, cetostearyl alcohol, cetyl esters wax, cocoabutter, cholesterol, dimethicone, glycerin, glyceryl monostearate,isopropyl myristate, isopropyl palmitate, kaolin, lecithin, lightmineral oil, mineral oil, mineral oil and lanolin alcohols, petrolatum,and petrolatum and lanolin alcohols.

The carrier can be any suitable aqueous dispersion material, cream,lotion, or ointment, which may include, for example hydrocolloids,plasdone, methyl cellulose, hydroxypropyl cellulose, lanolin, mineraloil, petroleum jelly, polyalkylene glycols such as polyethylene glycols,or mixtures thereof. The formulations may contain surfactants,antioxidants, and stabilizers such as benzoic acid, sorbic acid,parabens, butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), vitamin E, sarcosonates, and the like.

The benefit agents can also be combined with astringents such as witchhazel, aluminum acetate, aluminum sulfate, zinc oxide, zinc acetate,sodium bicarbonate, and calamine. One of the functions of theformulations when applied to contact dermatitis is to remove theirritant material from the skin. This requires astringent activity, andthe addition of aluminum acetate, zinc oxide, zinc acetate, sodiumbicarbonate, calamine, witch hazel, zinc carbonate, and aluminumhydroxide may be employed to enhance this physical property.

A preferred carrier material includes water, glycerin, cetyl palmitate,mineral oil, caprylic/capric triglyceride, octyldodecanol, cetylalcohol, glyceryl stearate, colloidal oat flour, dimethicone, PEG-40stearate, carbomer, sodium hydroxide, phenoxy ethanol, caramel IIIcoloring, DMDM hydantoin, and iodopropynyl butylcarbamate.

Glycerin, also called glycerol, acts as a humectant, skin protectant,and solvent present in all natural lipids (fats), whether animal orvegetable. Whether natural or synthetic, glycerin is a humectant andextremely hygroscopic, meaning it readily absorbs water from othersources, attracting water from the environment and from the lower layersof skin (dermis) and increasing the amount of water in the surfacelayers of skin. Another aspect of glycerin's benefit is that it is askin-identical ingredient, meaning it is a substance found naturally inskin. In that respect it is one of the many substances in skin that helpmaintain the outer barrier and prevent dryness or scaling. The Food andDrug Administration (FDA) includes glycerin on its list of direct foodadditives considered Generally Recognized As Safe (GRAS), and on itslist of approved indirect food additives. Glycerin is also anFDA-approved active ingredient in Over-the-Counter (OTC) skin protectantdrug products and ear drying products, and it is an approved demulcentfor the eyes.

Cetyl palmitate acts as an emollient, acting as a lubricant on theskin's surface, which gives the skin a soft and smooth appearance. Thepalmitates generally are esters of palmitic acid and ethylhexyl, cetyl,or isopropyl alcohol. In cosmetics and personal care products, they allfunction as skin conditioning agents and emollients. The palmitates areefficient opacifiers in cream and lotion shampoos. Isopropyl Palmitatealso functions as a binder. The safety of the palmitates has beenassessed by the Cosmetic Ingredient Review (CIR) Expert Panel. The CIRExpert Panel evaluated the scientific data and concluded that EthylhexylPalmitate, Cetyl Palmitate and Isopropyl Palmitate were safe as cosmeticingredients. In 2001, the CIR Expert Panel considered available new dataon Ethylhexyl, Cetyl and Isopropyl Palmitate and reaffirmed the aboveconclusion.

Light mineral oil acts as an emollient, skin protectant, and solvent.Mineral oil functions as an emollient skin conditioning agent, anocclusive skin protectant, and as a solvent. The FDA permits the use ofmineral oil as an active ingredient in the following OTC drug productcategories: anorectal drugs, skin protectants, and ophthalmicemollients.

Caprylic/capric triglyceride (CAS No. 124-07-2) acts as a moisturizer,viscosity modulator, inactive carrier, and stabilizer. Caprylic/caprictriglyceride is an oily liquid made from coconut oil. It is used incosmetics and other personal care products, such as face creams,lipstick, eye makeup and foundations. It can also be used in perfumes,moisturizers and sunscreens. It is found naturally in foods but can alsobe made by industrial processes. Caprylic/capric triglyceride has anumber of useful properties in the formulation of cosmetics and, inparticular, face creams. Caprylic/capric triglyceride creates a barrieron the skin's surface, decreasing the amount of moisture lost throughthe skin, functioning not only to prevent dryness in skin, but also as askin conditioning agent. It provides a slippery feeling and promotesdispersion of pigments in various colored cosmetics. Caprylic/caprictriglycerides have a low viscosity. This property allows it to alter thethickness of a particular cosmetic product. Adding caprylic/caprictriglycerides to thick face creams helps thin them out to the desiredthickness. Caprylic/capric trigylceride does not readily oxidize. It isparticularly useful as a stabilizer of emulsions. This property isparticularly useful in facial creams and other cosmetic products,helping to give them a longer shelf life. The Food and DrugAdministration lists caprylic/capric triglyceride as GenerallyRecognized As Safe, or GRAS, for use as a direct food additive. Inaddition, caprylic/capric triglyceride has been assessed by the CosmeticIngredient Review Expert Panel, which evaluated the scientific data andconcluded, and reaffirmed in 2001, that it was safe as it was being usedat that time. Similarly suitable triglyceride materials includemedium-chain triglyceride oil (CAS 65381-09-1) available as MCT oil fromAcme-Hardesty Oleochemicals.

Octyldodecanol (CAS No. 5333-42-6; Tegosoft® G20 available from Evonik)acts as a stabilizer, emulsifier, lubricant, and solvent. Octyldodecanolhelps to form emulsions and prevent an emulsion from separating into itsoil and liquid components. These ingredients also reduce the tendency offinished products to generate foam when shaken. When used in theformulation of skin care products, octyldodecanol acts as a lubricant onthe skin surface, which gives the skin a soft, smooth appearance. Thesafety of Octyldodecanol and related ingredients has been assessed bythe Cosmetic Ingredient Review (CIR) Expert Panel. The CIR Expert Panelevaluated the scientific data and concluded that octyldodecanol was safefor use in cosmetics and personal care products. In 2004, the CIR ExpertPanel considered available new data on octyldodecanol and reaffirmed theabove conclusion. Octyldodecanol may be used in cosmetics and personalcare products marketed in Europe according to the general provisions ofthe Cosmetics Directive of the European Union.

Cetyl alcohol (CAS No. 36653-82-4) acts as an emollients, thickeners,and emulsifier. Cetyl alcohol and the other fatty alcohols keep anemulsion from separating into its oil and liquid components. Theseingredients are also used to alter the thickness of liquid products andto increase foaming capacity or to stabilize foams. The safety of cetylalcohol has been assessed by the Cosmetic Ingredient Review (CIR) ExpertPanel. The CIR Expert Panel evaluated the scientific data and concludedthat this fatty alcohol was safe for use as a cosmetic ingredient. In2005, the CIR Expert Panel considered available new data on cetearylalcohol and the other fatty alcohols and reaffirmed the aboveconclusion. If they are derived from plants, cetearyl, cetyl,isostearyl, myristyl and behenyl alcohols may be used in cosmetics andpersonal care products marketed in Europe according to the generalprovisions of the Cosmetics Directive of the European Union. Ingredientsof animal origin must comply with European Union animal by-productsregulations.

Glyceryl stearate (CAS Nos. 11099-07-3, 31566-31-1) may act as anemulsifier, humectant, lubricant, or solvent. As an emulsifier itassists in forming neutral, stable emulsions; it is also a solvent,humectant, and consistency regulator in water-in-oil and oil-in-waterformulations. It is typically derived from palm kernel or soy oil forcosmetic use. Glyceryl stearate helps to form emulsions by reducing thesurface tension of the substances to be emulsified. The safety ofGlyceryl Stearate has been assessed by the Cosmetic Ingredient Review(CIR) Expert Panel. The CIR Expert Panel evaluated the scientific dataand concluded that Glyceryl Stearate was safe form use in cosmetics andpersonal care products. The CIR Expert Panel reviewed chronic studies ofglyceryl stearate that showed no adverse effects on reproduction, and nocarcinogenic effects. Human exposure studies of products containingglyceryl stearate and glyceryl stearate SE, as well as clinicalexperience, have shown these compounds to be non-sensitizing,non-phototoxic and non-photosensitizing. If they are made from plants,glyceryl stearate and glyceryl stearate SE may be used in cosmetics andpersonal care products marketed in Europe according to the generalprovisions of the Cosmetics Directive of the European Union. Ingredientsmade from animal sources must comply with the European Union animalby-products regulations. A suitable material is available from ProtameenChemicals Inc. under the trade name “Protachem GMS-450.”

Colloidal oat flour (CAS No. 281-672-4) may act as a moisturizer, skinprotectant, pH buffer, and anti-inflammatory agent, and may haveanti-irritant and anti-inflammatory properties. As a skin protectant,colloidal oatmeal temporarily protects injured or exposed skin fromharmful or annoying stimuli, and may therefore provide relief to theskin. Oatmeal has been used for centuries as a soothing agent to relieveitch and irritation associated with various xerotic dermatoses. In 1945,a ready to use colloidal oatmeal, produced by finely grinding the oatand boiling it to extract the colloidal material, became available.Today, colloidal oatmeal is available in various dosage forms frompowders for the bath to shampoos, shaving gels, and moisturizing creams.

Currently, the use of colloidal oatmeal as a skin protectant isregulated by the U.S. Food and Drug Administration (FDA) according tothe Over-The-Counter Final Monograph for Skin Protectant Drug Productsissued in June 2003. Its preparation is also standardized by the UnitedStates Pharmacopeia. The many clinical properties of colloidal oatmealderive from its chemical polymorphism. The high concentration instarches and beta-glucan is responsible for the protective andwater-holding functions of oat. The presence of different types ofphenols confers antioxidant and anti-inflammatory activity. Some of theoat phenols are also strong ultraviolet absorbers. The cleansingactivity of oat is mostly due to saponins. Its many functionalproperties make colloidal oatmeal a cleanser, moisturizer, buffer, aswell as a soothing and protective anti-inflammatory agent.

The Food and Drug Administration (FDA) reviewed the safety and efficacyof colloidal oatmeal and approved its use as an active ingredient inOver-the-Counter (OTC) skin protectant drug products at a minimumconcentration of 0.007%, or 0.003% when used in combination with mineraloil. When used as a skin protectant in an OTC skin protectant drugproduct, this ingredient must be called colloidal oatmeal. The CosmeticIngredient Review (CIR) has deferred evaluation of this ingredientbecause the safety has been assessed by FDA. This deferral of review isaccording to the provisions of the CIR Procedures. Avena Sativa (Oat)Kernel Meal and colloidal oatmeal may be used in cosmetics and personalcare products marketed in Europe according to the general provisions ofthe Cosmetics Directive of the European Union.

Dimethicone (CAS No. 9006-65-9) may act as a moisturizer and emollient.Dimethicone is a silicone based polymer that forms a protective barrieron the skin to help retain moisture. Dimethicone's oil-like consistencyalso gives it emollient properties. The Food and Drug Administration(FDA) reviewed the safety of dimethicone and approved its use as a skinprotectant active ingredient in over-the-counter (OTC) drug products.The safety of Dimethicone has been assessed by the Cosmetic IngredientReview (CIR) Expert Panel. The CIR Expert Panel evaluated the scientificdata and concluded that these ingredients were safe for use incosmetics. Dimethicone, methicone, and the related polymers may be usedin cosmetics and personal care products marketed in Europe according tothe general provisions of the Cosmetics Directive of the European Union.The World Health Organization Joint FAO/WHO Expert Committee on FoodAdditives has established an acceptable daily intake level forDimethylpolysiloxane (Dimethicone) of 0 to 1.5 mg/kg body weight.

PEG-40 stearate (CAS No. 9004-99-3) may act as an emulsifier. PEG-40stearate typically functions as a cleansing agent, but also helps keepingredients solubilized. Suitable materials include a PEG-40 stearateavailable from Lipo Chemicals Inc. under the trade name “Lipopeg® 39S.”The safety of the PEG stearates has been assessed by the CosmeticIngredient Review (CIR) Expert Panel. The CIR Expert Panel evaluated thescientific data and concluded that PEG-2, -6, -8, -12, -20, -32, -40,-50, -100 and -150 stearates are safe for use in cosmetics and personalcare products. In 2002, as part of the scheduled re-evaluation ofingredients, the CIR Expert Panel considered available new data on thePEG Stearates and reaffirmed the above conclusion. In the CIR SafetyReview, the PEG stearates, whose average number of ethylene oxidemonomers range from 2 to 150, were nonlethal at levels up to 10 g/kg.They gave evidence of only minimal skin irritation and minimal eyeirritation when tested at 100%. PEG-8, -40 and -100 stearates producedno significant changes in growth, histopathologic observations orhematologic values in long-term feeding studies. Multiple generationstudies of PEG-8 and -40 stearates were negative for effects onreproduction. Clinical studies on the PEG stearates indicated that theseingredients were neither irritants nor sensitizers at concentrations of25% or greater. There was no evidence of phototoxicity orphotosensitization of PEG-2 or -8 stearates. Because the smaller PEGstearates were not photosensitizing the CIR Expert Panel did not expectthe larger ingredients to be photosensitizing. The CIR Expert Panelconcluded that safety data on individual PEG stearates were sufficientfor a decision regarding the safety of the entire group.

Carbomer polymers may act a thickeners and formulation stabilizers.Carbomers are synthetic polymers of varying molecular weights that canbe used to thicken suspend and stabilize cosmetic formulations.Requiring very low concentrations, carbomers are often used to adjustthe viscosity of cosmetic preparations. They dry quickly and are notfilm forming. Carbomers as an ingredient family resist bacterial attackand do not readily support mold growth. Under normal conditions, gelsprepared with sodium carbomer neither prevent nor promote the growth ofmicroorganisms; therefore the addition of a suitable preservative systemis advisable. The safety of the Carbomer has been assessed by theCosmetic Ingredient Review (CIR) Expert Panel. The CIR Expert Panelevaluated the scientific data and concluded that carbomer polymers weresafe as ingredients in cosmetics and personal care products. In 2001, aspart of the scheduled re-evaluation of ingredients, the CIR Expert Panelconsidered available new data on carbomer polymers and reaffirmed theabove conclusion.

The CIR Expert Panel reviewed acute oral studies showing that carbomerpolymers have low toxicities when ingested. Minimal skin irritation andno to moderate eye irritation were observed. Subchronic feeding studieswith a carbomer polymer resulted in lower than normal body weights, butno abnormal changes were observed in the organs. Some gastrointestinalirritation and marked pigment deposition within specific cells in theliver, called Kupffer cells, were seen in studies with carbomer.Clinical studies with carbomers showed that these polymers have lowpotential for skin irritation and sensitization at concentrations up to100%. A carbomer polymer demonstrated low potential for phototoxicityand photo-contact allergenicity. The Carbomers may be used in cosmeticsand personal care products marketed in Europe according to the generalprovisions of the Cosmetics Directive of the European Union.

Sodium Hydroxide (CAS No. 1310-73-2) may function as a pH modulator, analkali used to neutralize acids in maintenance of pH of the cream. TheFood and Drug Administration (FDA) includes sodium hydroxide on its listof substances affirmed as Generally Recognized as Safe (GRAS) for directaddition to food. Sodium hydroxide, as well as calcium hydroxide, isalso approved as an indirect food additive for use as a defoaming agentin the manufacture of paper and paperboard used as food packaging.Sodium hydroxide is listed in the Cosmetics Directive of the EuropeanUnion (see Annex III) and may be used at the following concentrationsand pH values: 5% by weight in nail cuticle solvents, 2% by weight inhair straighteners for general use, 4.5% by weight in hair straightenersfor professional use, up to a pH 12.7 in depilatories, and up to pH 11in other uses as a pH adjuster. The nail cuticle solvents and thegeneral use hair straighteners containing these ingredients must belabeled “contains alkali, avoid contact with eyes, can cause blindness,keep out of reach of children.” The professional hair straighteners mustbe labeled “for professional use only, avoid contact with eyes, cancause blindness.” Depilatories containing these ingredients must includethe following on the label: “Keep out of reach of children, avoidcontact with eyes.”

Phenoxy ethanol (CAS No. 9004-78-8) may act as a preservative,anti-oxidant, or anti-microbial. Phenoxyethanol is used as apreservative in cosmetics. Phenoxyethanol prevents or retards microbialgrowth, and thus protects cosmetics and personal care products fromspoilage. It may also be used in fragrances. Phenoxyethanol is usuallysynthesized for commercial use but it can also be found naturally inproducts such as green tea. The CIR Expert Panel reviewed safety data onphenoxyethanol and noted that it was practically nontoxic via oral anddermal administration. In a subchronic oral study, increased weights ofsome organs were noted when high doses of phenoxyethanol wereadministered. The doses in this study were considered to be much higherthan those resulting from use of cosmetics and personal care productscontaining phenoxyethanol. In dermal laboratory studies, phenoxyethanoldid not cause any birth defects. Phenoxyethanol was not mutagenic. Inclinical studies, phenoxyethanol was neither a primary nor a cumulativeirritant, it did not cause delayed hypersensitivity, and was itnonphototoxic. Phenoxyethanol is listed as 2-Phenoxyethanol in Annex VI,Part 1 (preservative which cosmetic products may contain) of theCosmetics Directive of the European Union and may be used inconcentrations up to 1%.

Caramel Coloring III (CAS No. 8028-89-5) is a coloring agent derivedfrom heating edible sugar. In cosmetics and personal care products,caramel is used in the formulation of a wide variety of product types asa coloring agent. The Food and Drug Administration (FDA) includescaramel on its list of substances considered Generally Recognized AsSafe (GRAS) as a multipurpose food substance. FDA also lists caramel asa color additive exempt from certification. Caramel is determined to besafe for use in coloring cosmetics and personal care products, includingproducts applied to the lips and area of the eye. The CosmeticIngredient Review (CIR) has deferred evaluation of this ingredientbecause the safety has been assessed by FDA. This deferral of review isaccording to the provisions of the CIR Procedures. Caramel functions asa colorant in cosmetics and personal care products. To be used as acolorant in the United States, caramel must comply with FDAmanufacturing requirements. For example, only certain food-grade acids,alkalis, and salts may be used to assist carmelization, in amountsconsistent with good manufacturing practice. Caramel is listed in AnnexIV, Part I (coloring agent allowed for use in cosmetic products) of theCosmetics Directive of the European Union and may be used withoutrestriction when purity requirements included in food regulations arefulfilled.

DMDM Hydantoin (e.g., Glydant® Plus available from Lonza) may functionas a preservative and anti-microbial. It is used as an antimicrobialformaldehyde releaser preservative with the trade name Glydant. DMDMhydantoin is an organic compound belonging to a class of compounds knownas hydantoins. It is used in the cosmetics industry and found inproducts like shampoos, hair conditioners, hair gels and skin careproducts. DMDM hydantoin works as a preservative because the releasedformaldehyde makes the environment less favorable to the microorganisms.The Cosmetic Ingredient Review (CIR) Expert Panel has evaluated DMDMhydantoin and concluded that it was safe to a great majority ofconsumers but has limited the concentration to 0.2% free formaldehydedue to the skin sensitivity of some individuals to this agent. A studyfound “[a]n increase in the use of DMDM hydantoin in cosmetic productswill also inevitably increase the risk of cosmetic dermatitis inconsumers allergic to formaldehyde.

The CIR Safety Review determined DMDM hydantoin is poorly absorbed fromthe skin. In a laboratory study, oral exposure to DMDM hydantoin did notresult in any adverse effects. The CIR Expert Panel noted that DMDMhydantoin is a formaldehyde donor in aqueous media. They attributedpositive results in some in vitro mutagenicity studies to formaldehyderelease. In these studies, the concentrations of DMDM hydantoin testedwere higher than those used in cosmetic and personal care products,likely resulting in much higher concentrations of formaldehyde thanfound in products. Clinical studies revealed some observations of skinirritation which could also be related to the release of formaldehydefrom DMDM hydantoin. The CIR Expert Panel has reviewed the safety offormaldehyde in cosmetics and personal care products and concluded thatit was safe to a great majority of consumers but has limited theconcentration to 0.2% free formaldehyde due to the skin sensitivity ofsome individuals to this agent. The amount of DMDM hydantoin required topreserve a product (less than 1%) does not expose the consumer toconcentrations of formaldehyde above the 0.2% limit for formaldehyderecommended by the CIR Expert Panel.

DMDM hydantoin, called dimethylol, dimethylhydantoin[1,3-Bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione], is listedin Annex VI, Part I (preservatives which cosmetics products may contain)of the Cosmetics Directive of the European Union and may be used incosmetics and personal care products at a maximum concentration of 0.6%.If the concentration of released formaldehyde exceeds 0.05% in thefinished product it must be labeled “contains formaldehyde.”

Iodopropynyl Butylcarbamate (CAS No. 55406-53-6) may function as apreservative, anti-microbial, and anti-fungal. The active ingredient ofthis product, IPBC, is recognized by the CTFA in the USA for use incosmetic and personal care products and listed by the EU as an approvedcosmetic preservative. IPBC-II is a colorless to light yellow, clearviscous liquid at room temperature. It is a unique and cost effectivepreservative that provides a high level of antimicrobial activity. It isremarkably proficient in inhibiting the growth of yeasts and molds. IPBCis compatible with essentially all cosmetic ingredients, such assurfactants, emulsifiers, proteins and herbal extracts.

Methods of Preparation

The compositions in general are prepared from the imidazole compound andcolloidal oatmeal, as well as any other desired benefit agents. Ifdesired additional ingredients such as surfactants and emulsifyingagents, antihistamines, topical anesthetics, topical antipruritics,astringents, and emollients may be added. The ingredients may be addedin such steps and amounts and processing varied as to create a spray,cream, gel, ointment, or lotion.

The advantages of the invention and specific embodiments of the skincare compositions prepared in accordance with the present invention areillustrated by the following examples. It will be understood, however,that the invention is not confined to the specific limitations set forthin the individual examples, but rather defined within the scope of theappended claims.

EXAMPLES Example 1

A topical formulation containing 100 mg of THI in 10 g of base cream wasprepared as follows. To 1.0 g of base cream (water, glycerin, mineraloil, cetyl palmitate, caprylic/capric triglyceride, octyldodecanol,cetyl alcohol, glyceryl stearate, colloidal oat flour, dimethicone,PEG-40 stearate, carbomer, sodium hydroxide, phenoxy ethanol, caramelIII coloring, DMDM hydantoin, iodopropynyl butylcarbamate) was added 100mg of THI (CAS No. 94944-70-4) portionwise with levigation of the powderbetween additions. A smooth cream was obtained by levigation in a marblemortar and pestle. A dime-sized portion of the levigated material wasthen incorporate geometrically with similar-sized portions of base andmixed thoroughly. Geometric mixing with additional cream base wasrepeated until 9.9 g of base was incorporated, yielding a 1.0% THIcream. Examination of the cream on a mixing plate suggested the THI wasat least partially dissolving in the cream base. Application of thefinished cream to the skin left no residue.

Example 2 Eczema/Psoriasis Lotion Treatment

The treatment test regime consists of three concentrations ranging from0.5% to 2% of the active ingredient THI. Affected areas are documentedwith before and after photos and notes of observations from each step inthe treatment regime are recorded. Three lotions respectively containing0.5% (Disc “A”), 1.0% (Disc “B”), and 2% (Disc “C”) by weight of THI areused in the treatment test.

Standard Application Protocol

The area to which the lotion is to be applied to is cleaned beforestarting treatment. The lotion from Disc “A” is applied to just coverthe affected area twice a day, once in morning and once again inevening. Any physical changes observed are noted; the treatment isdiscontinued if redness occurs. This regime is continued for one week.If the desired effect is realized at this concentration, applications at0.5% concentration are continued without moving on to the next higherconcentration. The treatment is discontinued if redness occurs.

At the start of week two if no observed relief is noticed with 0.5%lotion from Disc “A”, treatment is begun with 1.0% lotion from Disc “B”.The application regime just described is repeated substituting the 1.0%lotion from disc “B” for one week. If the desired effect is realized at1.0% concentration, the applications are continued at this concentrationwithout moving on to the next higher concentration, Any physical changesobserved are noted; the treatment is discontinued if redness occurs.

At the start of week three if no observed relief is noticed with 1.0%lotion from Disc “B”, treatment is begun with 2.0% lotion from Disc “C”.The application regime just described is repeated substituting the 2.0%lotion from disc “C” for one week. If the desired effect is realized at2.0% concentration, the applications are continued at thisconcentration. Any physical changes observed are noted; the treatment isdiscontinued if redness occurs.

Example 3 Test Case for Excema

The subject is a 10-year-old Caucasian male, in otherwise excellenthealth, suffering from excema over a portion of the subject's thighs.The subject rated the severity of the excema before treatment accordingto the protocol of Example 2 as 9 on a scale of 0 to 10, where 0represents no psoriasis or excema, and 10 represents extremely badpsoriasis or excema. The subject had been previously treated with locoidlipid oil and hyderm topical hydrocortisone treatments with little tomoderate success. The subject rated the effectiveness of the locoidlipid oil as 2 and of the hyderm cream as 4 on a scale of 1 to 5, where1 represents an extremely useful treatment, and 5 represents no changein symptoms. After following the treatment protocol of Example 2 usingonly the 0.5% concentration lotion, the subject rated the severity ofexcema after treatment as 0.

Example 4 Test Case for Psoriasis

The subject is a 63-year-old Caucasian male, apparently in otherwisegood health, suffering from psoriasis over a portion of the subject'schest and lower back. The subject had been suffering from moderate tosevere psoriasis in these areas for more than 40 years and was able toobtain only moderate relief during that time from a variety oftreatments including UV radiation, and at the time immediately prior tothe treatment according to the protocol of Example 2 had been takingmethotrexate orally and applying Daivonet or Daivonex ointmentstopically. Following the treatment protocol of Example 2 for two weeksand three weeks concluding with the 2.0% concentration lotionsubstantially relieved the subject's psoriatic symptoms.

What is claimed:
 1. A pharmaceutical, dermatologic, or cosmeticcomposition comprising colloidal oatmeal and 0.01% to 10% by weight of2-acetyl-4-tetrahydroxybutylimidazole or a pharmaceutically,dermatologically, or cosmetically acceptable salt thereof, contained ina dermatologically acceptable carrier.
 2. The composition of claim 1, inthe form of a spray, cream, gel, lotion, or ointment.
 3. The compositionof claim 1, wherein the carrier comprises one or more excipientsselected from the group consisting of surfactants, solvents, tonicitymodifiers, thickeners, emulsifiers, preservatives, dispersants, buffers,stabilizers, fragrances, colorants, and flavorings.
 4. The compositionof claim 1, further comprising one or more compounds or compositionsselected from the group consisting of antipruritics, emollients,antiseptics, antifungals, antiinflammatories, immunosuppressants,psoriasis agents, anti-cancer agents, antibiotics, antiparasitics,antioxidants, antibacterials, antimicrobials, antiretrovirals,moisturizers, sunscreens, NSAIDs, hormones, steroids, analgesics,antihistamines, and antipyretics.
 5. The composition of claim 1,comprising 0.01% to 25% by weight of the colloidal oatmeal.
 6. Thecomposition of claim 5, comprising 0.1% to 5% by weight of2-acetyl-4-tetrahydroxybutylimidazole or a pharmaceutically,dermatologically, or cosmetically acceptable salt thereof and 0.1% to10% by weight of the colloidal oatmeal.
 7. The composition of claim 6,comprising 0.5% to 2% by weight of 2-acetyl-4-tetrahydroxybutylimidazoleor a pharmaceutically, dermatologically, or cosmetically acceptable saltthereof and 0.5% to 2% by weight of the colloidal oatmeal.